Amide derivatives as glycogen synthase kinase 3-β inhibitors

ABSTRACT

This invention concerns a compound of formula 
                         
a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein ring A represents a 6-membered heterocycle; R 1  is hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; optionally substituted C 1-6 alkyl; C 1-6 alkyloxycarbonyl; optionally substituted C 1-6 alkyloxyC 1-6 alkylcarbonyl; X is a direct bond or a linker atom or group; Z is O or S; R 2  is hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, a carbocycle or a heterocycle, each of said groups may optionally be substituted; R 3  is hydrogen; hydroxy; halo; optionally substituted C 1-6 alkyl or C 2-6 alkenyl or C 2-6 alkynyl; C 1-6 alkyloxy; C 1-6 alkylthio; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(C 1-6 alkyl)amino; polyhaloC 1-6 alkyl; polyhaloC 1-6 alkyloxy; polyhaloC 1-6 alkylthio; R 21 ; R 21 —C 1-6 alkyl; R 21 —O—; R 21 —S—; R 21 —C(═O)—; R 21 —S(═O) p —; R 7 —S(═O) p —; R 7 —S(═O) p —NH—; R 21 —S(═O) p —NH—; R 7 —C(═O)—; —NHC(═O)H; —C(═O)NHNH 2 ; R 7 —C(═O)—NH—; R 21 —C(═O)—NH—; —C(═NH)R 7 ; —C(═NH)R 21 ; R 4a  or R 4b  each independently represent hydrogen, R 8 , —Y 1 —NR 9 —Y 2 —NR 10 R 11 , —Y 1 —NR 9 —Y 1 —R 8 , —Y 1 —NR 9 R 10 ; provided that —X—R 2  and/or R 3  is other than hydrogen; their use, pharmaceutical compositions comprising them and processes for their preparation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national stage of Application No.PCT/EP02/12067, filed Oct. 29, 2002, which application claims priorityfrom EP 01204193.5 filed Nov. 1, 2001.

The present invention concerns a novel group of compounds, their use asa medicine, their use for the manufacture of a medicament for thetreatment of diseases mediated through glycogen synthase kinase 3, inparticular glycogen synthase kinase 3β; processes for their preparationand pharmaceutical compositions comprising them.

WO 97/19065 discloses substituted 2-anilinopyrimidines useful asp56^(lck), p59^(fyn), ZAP-70 and protein kinase C inhibitors.

WO 00/62778 describes cyclic protein tyrosine kinase inhibitors.

The present invention relates to compounds which are distinguishablefrom the prior art in structure, pharmacological activity, potency orselectivity.

SUMMARY OF THE INVENTION

The present invention concerns a compound of formula (I)

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein

-   Z represents O or S;-   ring A is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl;-   R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;    C₁₋₆alkyloxyC₁₋₆alkylcarbonyl optionally substituted with    C₁₋₆alkyloxycarbonyl;-   X is —NR¹—; —NH—NH—; —N═N—; —O—; —C(═O)—; —C(═S)—; —O—C(═O)—;    —C(═O)—O—; —O—C(═O)—C₁₋₆alkyl-; —C(═O)—O—C₁₋₆alkyl-;    —O—C₁₋₆alkyl-C(═O)—; —C(═O)—C₁₋₆alkyl-O—; —O—C(═O)—NR¹—;    —NR¹—C(═O)—O—; —O—C(═O)—C(═O)—; —C(═O)—NR¹—, —NR¹—C(═O)—;    —C(═S)—NR¹—, —NR¹—C(═S)—; —NR¹—C(═O)—NR¹—; —NR¹—C(═S)—NR¹—;    —NR¹—S(═O)—NR¹—; —NR¹—S(═O)₂—NR¹—; —C₁₋₆alkyl-C(═O)—NR¹—;    —O—C₁₋₆alkyl-C(═O)—NR¹—; —C₁₋₆alkyl-O—C(═O)—NR¹—; —C₁₋₆alkyl-;    —O—C₁₋₆alkyl-; —C₁₋₆alkyl-O—; —NR¹—C₁₋₆alkyl-; —C₁₋₆alkyl-NR¹—;    —NR¹—C₁₆alkyl-NR¹—; —NR¹—C₁₋₆alkyl-C₃₋₇cycloalkyl-; —C₂₋₆alkenyl-;    —C₂₋₆alkynyl-; —O—C₂₋₆alkenyl-; —C₂₋₆alkenyl-O—; —NR¹—C₂₋₆alkenyl-;    —C₂₋₆alkenyl-NR¹—;—NR¹—C₂₋₆alkenyl-NR¹—;    —NR¹—C₂₋₆alkenyl-C₃₋₇cycloalkyl-; —O—C₂₋₆alkynyl-; —C₂₋₆alkynyl-O—;    —NR¹—C₂₋₆alkynyl-; —C₂₋₆alkynyl-NR¹—; —NR¹—C₂₋₆alkynyl-NR¹—;    —NR¹—C₂₋₆alkynyl-C₃₋₇cycloalkyl-; —O—C₁₋₆alkyl-O—;    —O—C₂₋₆alkenyl-O—; —O—C₂₋₆alkynyl-O—; —CHOH—; —S—; —S(═O)—;    —S(═O)₂—; —S(═O)—NR¹—; —S(═O)₂—NR¹—; —NR¹—S(═O)—; —NR¹—S(═O)₂—;    —S—C₁₋₆alkyl-; —C₁₋₆alkyl-S—; —S—C₂₋₆alkenyl-; —C₂₋₆alkenyl-S—;    —S—C₂₋₆alkynyl-; —C₂₋₆alkynyl-S—; —O—C₁₋₆alkyl-S(═O)₂— or a direct    bond;-   R² is hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, R²⁰, each of    said groups representing R² may optionally be substituted where    possible with one or more substituents each independently being    selected from ═S; ═O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵—O—; SH;    R¹⁵—S—; formyl; carboxyl; R¹⁵—C(═O)—; R¹⁵—O—C(═O)—; R¹⁵—C(═O)—O—;    R¹⁵—O—C(═O)—O—; —SO₃H; R¹⁵—S(═O)—; R¹⁵—S(═O)₂—; R⁵R⁶N;    R⁵R⁶N—C₁₋₆alkyl; R⁵R⁶N—C₃₋₇cycloalkyl; R⁵R⁶N—C₁₋₆alkyloxy;    R⁵R⁶N—C(═O)—; R⁵R⁶N—C(═S)—; R⁵R⁶N—C(═O)—NH—; R⁵R⁶N—C(═S)—NH—;    R⁵R⁶N—S(═O)_(n)—; R⁵R⁶N—S(═O)_(n)—NH—; R¹⁵—C(═S)—; R¹⁵—C(═O)—NH—;    R¹⁵—O—C(═O)—NH—; R¹⁵—S(═O)_(n)—NH—; R¹⁵—O—S(═O)_(n)—NH—;    R¹⁵—C(═S)—NH—; R¹⁵—O—C(═S)—NH—; R¹⁷R¹⁸N—Y_(1a)—;    R¹⁷R¹⁸N—Y₂—NR¹⁶—Y₁—; R¹⁵—Y₂—NR¹⁹—Y₁—; H—Y₂—NR¹⁹—Y₁—;-   R³ is hydrogen; hydroxy; halo; C₁₋₆alkyl; C₁₋₆alkyl substituted with    cyano, hydroxy or —C(═O)R⁷; C₂₋₆alkenyl; C₂₋₆alkenyl substituted    with one or more halogen atoms or cyano; C₂₋₆alkynyl; C₂₋₆alkynyl    substituted with one or more halogen atoms or cyano; C₁₋₆alkyloxy;    C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; carboxyl;    cyano; nitro; amino; mono- or di(C₁₋₆alkyl)amino; polyhaloC₁₋₆alkyl;    polyhaloC₁₋₆alkyloxy; polyhaloC₁₋₆alkylthio; R²¹; R²¹—C₁₋₆alkyl;    R²¹—O—; R²¹—S—; R²¹—C(═O)—; R²¹—S(═O)_(p)—; R⁷—S(═O)_(p)—;    R⁷—S(═O)_(p)—NH—; R²¹—S(═O)_(p)—NH—; R⁷—C(═O)—; —NHC(═O)H;    —C(═O)NHNH₂; R⁷—C(═O)—NH—; R²¹—C(═O)—NH—; —C(═NH)R⁷; —C(═NH)R²¹;-   R^(4a) or R^(4b) each independently are hydrogen, R⁸,    —Y₁—NR⁹—Y₂—NR¹⁰R¹¹, —Y₁—NR⁹—Y₁—R⁸, —Y₁—NR⁹R¹⁰;-   R⁵ and R⁶ each independently are hydrogen, R⁸, —Y₁—NR⁹—Y₂—NR¹⁰R¹¹,    —Y₁—NR⁹—Y₁—R⁸, —Y₁—NR⁹R¹⁰, or-   R⁵ and R⁶ may together with the nitrogen to which they are attached    form a saturated or partially saturated monocyclic 3 to 8 membered    heterocycle or an aromatic 4 to 8 membered monocyclic heterocycle,    each of said heterocycles may optionally be substituted with one or    more substituents selected from R¹², R¹³ and R¹⁴, or each of said    heterocycles may optionally be fused with a benzene ring, said    benzene ring being optionally substituted with one or more    substituents selected from R¹², R¹³ and R¹⁴;-   R⁷ is C₁₋₆alkyl, C₁₋₆alkyloxy, amino, mono- or di(C₁₋₆alkyl)amino or    polyhaloC₁₋₆alkyl;-   R⁸ is C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; a monocyclic, bicyclic or    tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic    partially saturated carbocycle; a monocyclic, bicyclic or tricyclic    aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated    heterocycle; a monocyclic, bicyclic or tricyclic partially saturated    heterocycle; a monocyclic, bicyclic or tricyclic aromatic    heterocycle; C₁₋₆alkyl substituted with a monocyclic, bicyclic or    tricyclic saturated carbocycle or with a monocyclic, bicyclic or    tricyclic partially saturated carbocycle or with a monocyclic,    bicyclic or tricyclic aromatic carbocycle or with a monocyclic,    bicyclic or tricyclic saturated heterocycle or with a monocyclic,    bicyclic or tricyclic partially saturated heterocycle or with a    monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said    groups representing R⁸ may optionally be substituted with one or    more substituents selected from R¹², R¹³ and R¹⁴;-   R⁹, R¹⁰ and R¹¹ each independently are hydrogen or R⁸, or-   any two of R⁹, R¹⁰ and R¹¹ may together be C₁₋₆alkanediyl or    C₂₋₆alkenediyl thereby forming a saturated or partially saturated    monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8    membered monocyclic heterocycle together with the nitrogen atoms to    which they are attached, each of said heterocycles may optionally be    substituted with one or more substituents selected from R¹², R¹³ and    R¹⁴;-   R¹², R¹³ and R¹⁴ each independently are hydrogen; R¹⁵; hydroxy;    halo; nitro; cyano; R¹⁵—O—; SH; R¹⁵—S—; formyl; carboxyl;    R¹⁵—C(═O)—; R¹⁵—O—C(═O)—; R¹⁵—C(═O)—O—; R¹⁵—O—C(═O)—O—; —SO₃H;    R¹⁵—S(═O)—; R¹⁵—S(═O)₂—; R¹⁵R¹⁶N—S(═O)—; R¹⁵R¹⁶N—S(═O)₂—;    R¹⁷R¹⁸N—Y₁—; R¹⁷R¹⁸N—Y₂—NR¹⁶—Y₁—; R¹⁵—Y₂—NR¹⁹—Y₁—; H—Y₂—NR¹⁹—Y₁—;    oxo, or-   any two of R¹², R¹³ and R¹⁴ may together be C₁₋₆alkanediyl or    C₂₋₆alkenediyl thereby forming a saturated or partially saturated    monocyclic 3 to 8 membered carbo— or heterocycle or an aromatic 4 to    8 membered monocyclic carbo—or heterocycle together with the atoms    to which they are attached, or-   any two of R¹², R¹³ and R¹⁴ may together be —O—(CH₂)_(r)—O— thereby    forming a saturated, partially saturated or aromatic monocyclic 4 to    8 membered carbo—or heterocycle together with the atoms to which    they are attached;-   R¹⁵ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, a monocyclic, bicyclic    or tricyclic saturated carbocycle; a monocyclic, bicyclic or    tricyclic partially saturated carbocycle; a monocyclic, bicyclic or    tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic    saturated heterocycle; a monocyclic, bicyclic or tricyclic partially    saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic    heterocycle; C₁₋₆alkyl substituted with a monocyclic, bicyclic or    tricyclic saturated carbocycle or with a monocyclic, bicyclic or    tricyclic partially saturated carbocycle or with a monocyclic,    bicyclic or tricyclic aromatic carbocycle or with a monocyclic,    bicyclic or tricyclic saturated heterocycle or with a monocyclic,    bicyclic or tricyclic partially saturated heterocycle or with a    monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said    substituents representing R¹⁵ may optionally be substituted with one    or more substituents selected from R¹², R¹³ and R¹⁴; or each of said    carbocycles or heterocycles may optionally be fused with a benzene    ring, said benzene ring being optionally substituted with one or    more substituents selected from R¹², R¹³ and R¹⁴;-   R¹⁶,R¹⁷, R¹⁸ and R¹⁹ each independently are hydrogen or R¹⁵, or-   R¹⁷ and R¹⁸, or R¹⁵ and R¹⁹ may together be C₁₋₆alkanediyl or    C₂₋₆alkenediyl thereby forming a saturated or partially saturated    monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8    membered monocyclic heterocycle, each of said heterocycles may    optionally be substituted with one or more substituents selected    from R¹², R¹³ and R¹⁴; or-   R¹⁷ and R¹⁸ together with R¹⁶ may be C₁₋₆alkanediyl or    C₂₋₆alkenediyl thereby forming a saturated or partially saturated    monocyclic 3 to 8 membered heterocycle or an aromatic 4to 8 membered    monocyclic heterocycle together with the nitrogen atoms to which    they are attached, each of said heterocycles may optionally be    substituted with one or more substituents selected from R¹², R¹³ and    R¹⁴;-   R²⁰ is a monocyclic, bicyclic or tricyclic saturated carbocycle; a    monocyclic, bicyclic or tricyclic partially saturated carbocycle; a    monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic,    bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic    or tricyclic partially saturated heterocycle; a monocyclic, bicyclic    or tricyclic aromatic heterocycle;-   R²¹ is a monocyclic, bicyclic or tricyclic saturated carbocycle; a    monocyclic, bicyclic or tricyclic partially saturated carbocycle; a    monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic,    bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic    or tricyclic partially saturated heterocycle; a monocyclic, bicyclic    or tricyclic aromatic heterocycle, each of said carbocycles or    heterocycles representing R²¹ may optionally be substituted with one    or more substituents selected from R¹², R¹³ and R¹⁴;-   Y_(1a) is —Y₃—S(═O)—Y₄—; —Y₃—S(═O)₂—Y₄—, —Y₃—C(═O)—Y₄—,    —Y₃—C(═S)—Y₄—, —Y₃—O—Y₄—, —Y₃—S—Y₄—, —Y₃—O—C(═O)—Y₄— or    —Y₃—C(═O)—O—Y₄—;-   Y₁ or Y₂ each independently are a direct bond, —Y₃—S(═O)—Y₄—;    —Y₃—S(═O)₂—Y₄—, —Y₃—C(═O)—Y₄—, —Y₃—C(═S)—Y₄—, —Y₃—O—Y₄—, —Y₃—S—Y₄—,    —Y₃—O—C(═O)—Y₄— or —Y₃—C(═O)—O—Y₄—;-   Y₃ or Y₄ each independently are a direct bond, C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl;-   n is 1 or 2;-   m is 1 or 2;-   p is 1 or 2;-   r is 1 to 5;-   s is 1 to 3;-   aryl is phenyl or phenyl substituted with one, two, three, four or    five substituents each independently selected from halo, C₁₋₆alkyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl and    polyhaloC₁₋₆alkyloxy;-   provided that —X—R² and/or R³ is other than hydrogen; and-   provided that the following compounds-   N-methoxy-N-methyl-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinecarboxamide    and    N-phenyl-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinecarboxamide    are not included.

The present invention also relates to the use of a compound for themanufacture of a medicament for the prevention or the treatment ofdiseases mediated through GSK3, said compound being a compound offormula of formula (I′)

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein

-   Z represents O or S;-   ring A is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl;-   R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;    C₁₋₆alkyloxyC₁₋₆alkylcarbonyl optionally substituted with    C₁₋₆alkyloxycarbonyl;-   X is —NR¹—; —NH—NH—; —N═N—; —O—; —C(═O)—; —C(═S)—; —O—C(═O)—;    —C(═O)—O—; —O—C(═O)—C₁₋₆alkyl-; —C(═O)—O—C₁₋₆alkyl-;    —O—C₁₋₆alkyl-C(═O)—; —C(═O)—C₁₋₆alkyl-O—; —O—C(═O)—NR¹—;    —NR¹—C(═O)—O—; —O—C(═O)—C(═O)—; —C(═O)—NR¹—, —NR¹ —C(═O)—;    —C(═S)—NR¹—, —NR¹—C(═S)—; —NR¹ —C(═O)—NR¹—; —NR¹—C(═S)—NR¹—;    —NR¹—S(═O)—NR¹—; —NR¹—S(═O)₂—NR¹—; —C₁₋₆alkyl-C(═O)—NR¹—;    —O—C₁₋₆alkyl-C(═O)—NR¹—; —C₁₋₆alkyl-O—C(═O)—NR₁—; —C₁₋₆alkyl-;    —O—C₁₋₆alkyl-; —C₁₋₆alkyl-O—; —NR¹—C₁₋₆alkyl-; —C₁₋₆alkyl-NR¹—;    —NR¹—C₁₋₆alkyl-NR¹—; —NR¹—C₁₋₆alkyl-C₃₋₇cycloalkyl-; —C₂₋₆alkenyl-;    —C₂₋₆alkynyl-; —O—C₂₋₆alkenyl-; —C₂₋₆alkenyl-O—; —NR¹—C₂₋₆alkenyl-;    —C₂₋₆alkenyl-NR¹—; —NR¹—C₂₋₆alkenyl-NR¹—;    —NR¹—C₂₋₆alkenyl-C₃₋₇cycloalkyl-; —O—C₂₋₆alkynyl-; —C₂₋₆alkynyl-O—;    —NR¹—C₂₋₆alkynyl-; —C₂₋₆alkynyl-NR¹—; —NR¹—C₂₋₆alkynyl-NR¹—;    —NR¹—C₂₋₆alkynyl-C₃₋₇cycloalkyl-; —O—C₁₋₆alkyl-O—;    —O—C₂₋₆alkenyl-O—; —O—C₂₋₆alkynyl-O—; —CHOH—; —S—; —S(═O)—;    —S(═O)₂—; —S(═O)—NR¹—; —S(═O)₂—NR¹—; —NR¹—S(═O)—; —NR¹—S(═O)₂—;    —S—C₁₋₆alkyl-; —C₁₋₆alkyl-S—; —S—C₂₋₆alkenyl-; —C₂₋₆alkenyl-S—;    —S—C₂₋₆alkynyl-; —C₂₋₆alkynyl-S—; —O—C₁₋₆alkyl-S(═O)₂— or a direct    bond;-   R² is hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, R²⁰, each of    said groups representing R² may optionally be substituted where    possible with one or more substituents each independently being    selected from ═S; ═O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵—O—; SH;    R¹⁵—S—; formyl; carboxyl; R¹⁵—C(═O)—; R¹⁵—O—C(═O)—; R¹⁵—C(═O)—;    R¹⁵—O—C(═O)—; —SO₃H; R¹⁵—S(═O)—; R¹⁵—S(═O)₂—; R⁵R⁶N;    R⁵R⁶N—C₁₋₆alkyl; R⁵R⁶N—C₃₋₇cycloalkyl; R⁵R⁶N—C₁₋₆alkyloxy;    R⁵R⁶N—C(═O)—; R⁵R⁶N—C(═S)—; R⁵R⁶N—C(═O)—NH—; R⁵R⁶N—C(═S)—NH—;    R⁵R⁶N—S(═O)_(n)—; R⁵R⁶N—S(═O)_(n)—NH—; R¹⁵—C(═S)—; R¹⁵—C(═O)—NH—;    R¹⁵—O—C(═O)—NH—; R¹⁵—S(═O)_(n)—NH—; R¹⁵—O—S(═O)_(n)—NH—;    R¹⁵—C(═S)—NH—; R¹⁵—O—C(═S)—NH—; R¹⁷R¹⁸N—Y_(1a)—;    R¹⁷R¹⁸N—Y₂—NR¹⁶—Y₁—; R¹⁵—Y₂—NR¹⁹—Y₁—; H—Y₂—NR¹⁹—Y₁—;-   R³ is hydrogen; hydroxy; halo; C₁₋₆alkyl; C₁₋₆alkyl substituted with    cyano, hydroxy or —C(═O)R⁷; C₂₋₆alkenyl; C₂₋₆alkenyl substituted    with one or more halogen atoms or cyano; C₂₋₆alkynyl; C₂₋₆alkynyl    substituted with one or more halogen atoms or cyano; C₁₋₆alkyloxy;    C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; carboxyl;    cyano; nitro; amino; mono- or di(C₁₋₆alkyl)amino; polyhaloC₁₋₆alkyl;    polyhaloC₁₋₆alkyloxy; polyhaloC₁₋₆alkylthio; R²¹; R²¹—C₁₋₆alkyl;    R²¹—O—; R²¹—S—; R²¹—C(═O)—; R²¹—S(═O)_(p)—; R⁷—S(═O)_(p)—;    R⁷—S(═O)_(p)—NH—; R²¹—S(═O)_(p)—NH—; R⁷—C(═O)—; —NHC(═O)H;    —C(═O)NHNH₂; R⁷—C(═O)—NH—; R²¹—C(═O)—NH—; —C(═NH)R⁷; —C(═NH)R²¹;-   R^(4a) or R^(4b) each independently are hydrogen, R⁸,    —Y₁—NR⁹—Y₂—NR¹⁰R¹¹, —Y₁—NR⁹—Y₁—R⁸, —Y₁—NR⁹R¹⁰;-   R⁵ and R⁶ each independently are hydrogen, R⁸, —Y₁—NR⁹—Y₂—NR¹⁰R¹¹,    —Y₁—NR⁹—Y₁—R⁸, —Y₁—NR⁹R¹⁰, or-   R⁵ and R⁶ may together with the nitrogen to which they are attached    form a saturated or partially saturated monocyclic 3 to 8 membered    heterocycle or an aromatic 4 to 8 membered monocyclic heterocycle,    each of said heterocycles may optionally be substituted with one or    more substituents selected from R¹², R¹³ and R¹⁴, or each of said    heterocycles may optionally be fused with a benzene ring, said    benzene ring being optionally substituted with one or more    substituents selected from R¹², R¹³ and R¹⁴;-   R⁷ is C₁₋₆alkyl, C₁₋₆alkyloxy, amino, mono- or di(C₁₋₆alkyl)amino or    polyhaloC₁₋₆alkyl;-   R⁸ is C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; a monocyclic, bicyclic or    tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic    partially saturated carbocycle; a monocyclic, bicyclic or tricyclic    aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated    heterocycle; a monocyclic, bicyclic or tricyclic partially saturated    heterocycle; a monocyclic, bicyclic or tricyclic aromatic    heterocycle; C₁₋₆alkyl substituted with a monocyclic, bicyclic or    tricyclic saturated carbocycle or with a monocyclic, bicyclic or    tricyclic partially saturated carbocycle or with a monocyclic,    bicyclic or tricyclic aromatic carbocycle or with a monocyclic,    bicyclic or tricyclic saturated heterocycle or with a monocyclic,    bicyclic or tricyclic partially saturated heterocycle or with a    monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said    groups representing R⁸ may optionally be substituted with one or    more substituents selected from R¹², R¹³ and R¹⁴;-   R⁹, R¹⁰ and R¹¹ each independently are hydrogen or R⁸, or-   any two of R⁹, R¹⁰ and R¹¹ may together be C₁₋₆alkanediyl or    C₂₋₆alkenediyl thereby forming a saturated or partially saturated    monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8    membered monocyclic heterocycle together with the nitrogen atoms to    which they are attached, each of said heterocycles may optionally be    substituted with one or more substituents selected from R¹², R¹³ and    R¹⁴;-   R¹², R¹³ and R¹⁴ each independently are hydrogen; R¹⁵; hydroxy;    halo; nitro; cyano; R¹⁵—O—; SH; R¹⁵—S—; formyl; carboxyl;    R¹⁵—C(═O)—; R¹⁵—O—C(═O)—; R¹⁵—C(═O)—O—; R¹⁵—O—C(═O)—O—; —SO₃H;    R¹⁵—S(═O)—; R¹⁵—S(═O)₂—; R¹⁵R¹⁶N—S(═O)—; R¹⁵R¹⁶N—S(═O)₂—;    R¹⁷R¹⁸N—Y₁—; R¹⁷R¹⁸N—Y₂—NR¹⁶—Y₁—; R¹⁵—Y₂—NR¹⁹—Y₁—; H—Y₂—NR¹⁹—Y₁—;    oxo, or-   any two of R¹², R¹³ and R¹⁴ may together be C₁₋₆alkanediyl or    C₂₋₆alkenediyl thereby forming a saturated or partially saturated    monocyclic 3 to 8 membered carbo—or heterocycle or an aromatic 4 to    8 membered monocyclic carbo—or heterocycle together with the atoms    to which they are attached, or-   any two of R¹², R¹³ and R¹⁴ may together be —O—(CH₂)_(r)—O— thereby    forming a saturated, partially saturated or aromatic monocyclic 4 to    8 membered carbo—or heterocycle together with the atoms to which    they are attached;-   R¹⁵ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, a monocyclic, bicyclic    or tricyclic saturated carbocycle; a monocyclic, bicyclic or    tricyclic partially saturated carbocycle; a monocyclic, bicyclic or    tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic    saturated heterocycle; a monocyclic, bicyclic or tricyclic partially    saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic    heterocycle; C₁₋₆alkyl substituted with a monocyclic, bicyclic or    tricyclic saturated carbocycle or with a monocyclic, bicyclic or    tricyclic partially saturated carbocycle or with a monocyclic,    bicyclic or tricyclic aromatic carbocycle or with a monocyclic,    bicyclic or tricyclic saturated heterocycle or with a monocyclic,    bicyclic or tricyclic partially saturated heterocycle or with a    monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said    substituents representing R¹⁵ may optionally be substituted with one    or more substituents selected from R¹², R¹³ and R¹⁴; or each of said    carbocycles or heterocycles may optionally be fused with a benzene    ring, said benzene ring being optionally substituted with one or    more substituents selected from R¹², R¹³ and R¹⁴;-   R¹⁶, R¹⁷, R¹⁸ and R¹⁹ each independently are hydrogen or R¹⁵, or-   R¹⁷ and R¹⁸, or R¹⁵ and R¹⁹ may together be C₁₋₆alkanediyl or    C₂₋₆alkenediyl thereby forming a saturated or partially saturated    monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8    membered monocyclic heterocycle, each of said heterocycles may    optionally be substituted with one or more substituents selected    from R¹², R¹³ and R¹⁴; or-   R¹⁷ and R¹⁸ together with R¹⁶ may be C₁₋₆alkanediyl or    C₂₋₆alkenediyl thereby forming a saturated or partially saturated    monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8    membered monocyclic heterocycle together with the nitrogen atoms to    which they are attached, each of said heterocycles may optionally be    substituted with one or more substituents selected from R¹², R¹³ and    R¹⁴;-   R²⁰ is a monocyclic, bicyclic or tricyclic saturated carbocycle; a    monocyclic, bicyclic or tricyclic partially saturated carbocycle; a    monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic,    bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic    or tricyclic partially saturated heterocycle; a monocyclic, bicyclic    or tricyclic aromatic heterocycle;-   R²¹ is a monocyclic, bicyclic or tricyclic saturated carbocycle; a    monocyclic, bicyclic or tricyclic partially saturated carbocycle; a    monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic,    bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic    or tricyclic partially saturated heterocycle; a monocyclic, bicyclic    or tricyclic aromatic heterocycle, each of said carbocycles or    heterocycles representing R²¹ may optionally be substituted with one    or more substituents selected from R¹², R¹³ and R¹⁴;-   Y_(1a) is —Y₃—S(═O)—Y₄—; —Y₃—S(═O)₂—Y₄—, —Y₃—C(═O)—Y₄—,    —Y₃—C(═S)—Y₄—, —Y₃—O—Y₄—, —Y₃—S—Y₄—, —Y₃—O—C(═O)—Y₄— or    —Y₃—C(═O)—O—Y₄—;-   Y₁ or Y₂ each independently are a direct bond, —Y₃—S(═O)—Y₄—;    —Y₃—S(═O)₂—Y₄—, —Y₃—C(═O)—Y₄—, —Y₃—C(═S)—Y₄—, —Y₃—O—Y₄—, —Y₃—S—Y₄—,    —Y₃—O—C(═O)—Y₄— or —Y₃—C(═O)—O—Y₄—;-   Y₃ or Y₄ each independently are a direct bond, C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl;-   n is 1 or 2;-   m is 1 or 2;-   p is 1 or 2;-   r is 1 to 5;-   s is 1 to 3;-   aryl is phenyl or phenyl substituted with one, two, three, four or    five substituents each independently selected from halo, C₁₋₆alkyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl and    polyhaloC₁₋₆alkyloxy;-   provided that —X—R² and/or R³ is other than hydrogen.

DETAILED DESCRIPTION OF THE INVENTION

As used herein C₁₋₃alkyl as a group or part of a group defines straightor branched chain saturated hydrocarbon radicals having from 1 to 3carbon atoms such as methyl, ethyl, propyl, 1-methylethyl; C₁₋₄alkyl asa group or part of a group defines straight or branched chain saturatedhydrocarbon radicals having from 1 to 4 carbon atoms such as the groupsdefined for C₁₋₃alkyl and butyl; C₁₋₆alkyl as a group or part of a groupdefines straight or branched chain saturated hydrocarbon radicals havingfrom 1 to 6 carbon atoms such as the groups defined for C₁₋₄alkyl andpentyl, hexyl, 2-methylbutyl and the like; C₁₋₁₀alkyl as a group or partof a group defines straight or branched chain saturated hydrocarbonradicals having from 1 to 10 carbon atoms such as the groups defined forC₁₋₆alkyl and heptyl, octyl, nonyl, decyl and the like; C₁₋₆alkanediylas a group or part of a group defines bivalent straight or branchedchain saturated hydrocarbon radicals having from 1 to 6 carbon atomssuch as methylene, 1,2-ethane-diyl or 1,2-ethylidene, 1,3-propanediyl or1,3-propylidene, 1,4-butanediyl or 1,4-butylidene and the like;C₂₋₆alkenyl defines straight and branched chain hydrocarbon radicalshaving from 2 to 6 carbon atoms containing a double bond such asethenyl, propenyl, butenyl, pentenyl, hexenyl and the like; C₂₋₁₀alkenyldefines straight and branched chain hydrocarbon radicals having from 2to 10 carbon atoms containing a double bond such as the groups definedfor C₂₋₆alkenyl and heptenyl, octenyl, nonenyl, decenyl and the like;C₂₋₆alkenediyl defines bivalent straight and branched chain hydrocarbonradicals having from 2 to 6 carbon atoms containing one or more doublebonds such as ethenediyl, propenediyl, butenediyl, pentenediyl,hexenediyl and the like; C₂₋₆alkynyl defines straight and branched chainhydrocarbon radicals having from 2 to 6 carbon atoms containing a triplebond such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like;C₂₋₁₀alkynyl defines straight and branched chain hydrocarbon radicalshaving from 2 to 10 carbon atoms containing a triple bond such as thegroups defined for C₂₋₆alkynyl and heptynyl, octynyl, nonynyl, decynyland the like; C₂₋₆alkynediyl defines bivalent straight and branchedchain hydrocarbon radicals having from 2 to 6 carbon atoms containing atriple bond such as ethynediyl, propynediyl, butynediyl, pentynediyl,hexynediyl and the like; C₃₋₇cycloalkyl is generic to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; a monocyclic,bicyclic or tricyclic saturated carbocycle represents a ring systemconsisting of 1, 2 or 3 rings, said ring system being composed of onlycarbon atoms and said ring systemcontaining only single bonds; amonocyclic, bicyclic or tricyclic partially saturated carbocyclerepresents a ring system consisting of 1, 2 or 3 rings, said ring systembeing composed of only carbon atoms and comprising at least one doublebond provided that the ring system is not an aromatic ring system; amonocyclic, bicyclic or tricyclic aromatic carbocycle represents anaromatic ring system consisting of 1, 2 or 3 rings, said ring systembeing composed of only carbon atoms; the term aromatic is well known toa person skilled in the art and designates cyclically conjugated systemsof 4n′+2 electrons, that is with 6, 10, 14 etc. π-electrons (rule ofHückel; n′ being 1, 2, 3 etc.); a monocyclic, bicyclic or tricyclicsaturated heterocycle represents a ring system consisting of 1, 2 or 3rings and comprising at least one heteroatom selected from O, N or S,said ring system containing only single bonds; a monocyclic, bicyclic ortricyclic partially saturated heterocycle represents a ring systemconsisting of 1, 2 or 3 rings and comprising at least one heteroatomselected from O, N or S, and at least one double bond provided that thering system is not an aromatic ring system; a monocyclic, bicyclic ortricyclic aromatic heterocycle represents an aromatic ring systemconsisting of 1, 2 or 3 rings and comprising at least one heteroatomselected from O, N or S.

Particular examples of monocyclic, bicyclic or tricyclic saturatedcarbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, bicyclo[4,2,0]octanyl, cyclononanyl,cyclodecanyl, decahydronapthalenyl, tetradecahydroanthracenyl.

Particular examples of monocyclic, bicyclic or tricyclic partiallysaturated carbocycles are cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[4,2,0]octenyl,cyclononenyl, cyclodecenyl, octahydronaphthalenyl,1,2,3,4-tetrahydronaphthalenyl,1,2,3,4,4a,9,9a,10-octahydro-anthracenyl.

Particular examples of monocyclic, bicyclic or tricyclic aromaticcarbocycles are phenyl, naphthalenyl, anthracenyl.

Particular examples of monocyclic, bicyclic or tricyclic saturatedheterocycles are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl,imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydrooxazolyl,isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl,thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl,hexahydropyrazinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl,piperazinyl, trithianyl, decahydroquinolinyl, octahydroindolyl.

Particular examples of monocyclic, bicyclic or tricyclic partiallysaturated heterocycles are pyrrolinyl, imidazolinyl, pyrazolinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, indolinyl and the like.

Particular examples of monocyclic, bicyclic or tricyclic aromaticheterocycles are azetyl, oxetylidenyl, pyrrolyl, furyl, thienyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuryl, isobenzofuryl,benzothienyl, isobenzothienyl, indolizinyl, indolyl, isoindolyl,benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl,benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl,benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthiridinyl,pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl,isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl,pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl,furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl,isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl,imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl,furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl,isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl,imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl,furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl,isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl,imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl,triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl,triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl,triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl,triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl,imidazoimidazolyl, isoxazolotriazinyl, isothiazolotriazinyl,pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl,imidazotriazinyl, oxadiazolotriazinyl, thiadiazolotriazinyl,triazolotriazinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide moiety when attached to a sulfuratom and a sulfonyl moiety when two of said terms are attached to asulfur atom.

The term halo is generic to fluoro, chloro, bromo and iodo. As used inthe foregoing and hereinafter, polyhalomethyl as a group or part of agoup is defined as mono- or polyhalosubstituted methyl, in particularmethyl with one or more fluoro atoms, for example, difluoromethyl ortrifluoromethyl; polyhaloC₁₋₆alkyl as a group or part of a group isdefined as mono- or polyhalosubstituted C₁₋₆alkyl, for example, thegroups defined in halomethyl, 1,1-difluoro-ethyl and the like. In casemore than one halogen atoms are attached to an alkyl group within thedefinition of polyhalomethyl or polyhaloC₁₋₆alkyl, they may be the sameor different.

The term heterocycle as in the definition of for instance R², R⁵, R⁶, R⁸or R¹⁵ is meant to include all the possible isomeric forms of theheterocycles, for instance, pyrrolyl also includes 2H-pyrrolyl.

The hereinabove-mentioned carbocycles may be attached to the remainderof the molecule of formula (I) or (I′) through any ring carbon asappropriate, if not otherwise specified. Thus, for example, when thepartially saturated bicyclic carbocycle is1,2,3,4-tetrahydronaphthalenyl, it may be1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl andthe like.

The hereinabove-mentioned heterocycles may be attached to the remainderof the molecule of formula (I) or (I′) through any ring carbon orheteroatom as appropriate, if not otherwise specified. Thus, forexample, when the aromatic monocyclic heterocycle is imidazolyl, it maybe 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.

When any variable (eg. R⁵, R⁶ etc.) occurs more than one time in anyconstituent each definition is independent.

Lines drawn into ring systems from substituents indicate that the bondmay be attached to any of the suitable ring atoms.

For therapeutic use, salts of the compounds of formula (I) or (I′) arethose wherein the counterion is pharmaceutically acceptable. However,salts of acids and bases which are non-pharmaceutically acceptable mayalso find use, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic acid additionsalt forms which the compounds of formula (I) or (I′) are able to form.The latter can conveniently be obtained by treating the base form withsuch appropriate acids as inorganic acids, for example, hydrohalicacids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid;nitric acid; phosphoric acid and the like; or organic acids, forexample, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic,2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic,tartaric, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic,ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic,cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and thelike acids. Conversely the salt form can be converted by treatment withalkali into the free base form.

The compounds of formula (I) or (I′) containing acidic protons may beconverted into their therapeutically active non-toxic metal or amineaddition salt forms by treatment with appropriate organic and inorganicbases. Appropriate base salt forms comprise, for example, the ammoniumsalts, the alkali and earth alkaline metal salts, e.g. the lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. primary, secondary and tertiary aliphatic andaromatic amines such as methylamine, ethylamine, propylamine,isopropylamine, the four butylamine isomers, dimethylamine,diethylamine, diethanolamine, dipropylamine, diisopropylamine,di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine,triethylamine, tripropylamine, quinuclidine, pyridine, quinoline andisoquinoline, the benzathine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.Conversely the salt form can be converted by treatment with acid intothe free acid form.

The term addition salt also comprises the hydrates and solvent additionforms which the compounds of formula (I) or (I′) are able to form.Examples of such forms are e.g. hydrates, alcoholates and the like.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds of formula (I) or (I′) are able toform by reaction between a basic nitrogen of a compound of formula (I)or (I′) and an appropriate quaternizing agent, such as, for example, anoptionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g.methyliodide or benzyliodide. Other reactants with good leaving groupsmay also be used, such as alkyl trifluoromethanesulfonates, alkylmethanesulfonates, and alkyl p-toluenesulfonates. A qua ternary aminehas a positively charged nitrogen. Pharmaceutically acceptablecounterions include chloro, bromo, iodo, trifluoroacetate and acetate.The counterion of choice can be introduced using ion exchange resins.

It will be appreciated that some of the compounds of formula (I) or (I′)and their N-oxides, addition salts, quaternary amines andstereochemically isomeric forms may contain one or more centers ofchirality and exist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible stereoisomeric forms which the compounds of formula (I)or (I′), and their N-oxides, addition salts, quaternary amines orphysiologically functional derivatives may possess. Unless otherwisementioned or indicated, the chemical designation of compounds denotesthe mixture of all possible stereochemically isomeric forms, saidmixtures containing all diastereomers and enantiomers of the basicmolecular structure as well as each of the individual isomeric forms offormula (I) or (I′) and their N-oxides, salts, solvates or quaternaryamines substantially free, i.e. associated with less than 10%,preferably less than 5%, in particular less than 2% and most preferablyless than 1% of the other isomers. In particular, stereogenic centersmay have the R- or S-configuration; substituents on bivalent cyclic(partially) saturated radicals may have either the cis- ortrans-configuration. Compounds encompassing double bonds can have an Eor Z-stereochemistry at said double bond. Stereochemically isomericforms of the compounds of formula (I) or (I′) are obviously intended tobe embraced within the scope of this invention.

The N-oxide forms of the present compounds are meant to comprise thecompounds of formula (I) wherein one or several tertiary nitrogen atomsare oxidized to the so-called N-oxide.

Some of the compounds of formula (I) or (I′) may also exist in theirtautomeric form (e.g. keto-enol tautomerie). Such forms although notexplicitly indicated in the above formula are intended to be includedwithin the scope of the present invention.

Whenever used hereinafter, the term “compounds of formula (I)” or“compounds of formula (I) or (I′) is meant to also include their N-oxideforms, their salts, their quaternary amines and their stereochemicallyisomeric forms. Of special interest are those compounds of formula (I)or (I′) which are stereochemically pure.

Particular compounds are those compounds of formula (I) or (I′) asdefined hereinabove provided that the molecular mass of the compounds isat most 1000 u, in particular at most 800 u, more in particular at most700 u (u stands for unified atomic mass unit and equals 1.66×10⁻²⁷ kg).

Also particular interesting compounds are those compounds of formula (I)or (I′) as defined hereinabove, their N-oxides, pharmaceuticallyacceptable addition salts, quaternary amines and stereochemicallyisomeric forms thereof, wherein

-   Z represents O or S;-   ring A is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl;-   R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;    C₁₋₆alkyloxyC₁₋₆alkylcarbonyl optionally substituted with    C₁₋₆alkyloxycarbonyl;-   X is —NR¹—; —NH—NH—; —N═N—; —O—; —C(═O)—; —C(═S)—; —O—C(═O)—;    —C(═O)—O—; —O—C(═O)—C₁₋₆alkyl-; —C(═O)—O—C₁₋₆alkyl-;    —O—C₁₋₆alkyl-C(═O)—; —C(═O)—C₁₋₆alkyl-O—; —O—C(═O)—NR¹—;    —NR¹—C(═O)—O—; —O—C(═O)—C(═O)—; —C(═O)—NR¹—, —NR¹—C(═O)—;    —C(═S)—NR¹—, —NR¹—C(═S)—; —NR¹—C(═O)—NR¹—; —NR¹—C(═S)—NR¹—;    —NR¹—S(═O)—NR¹—; —NR¹—S(═O)₂—NR¹—; —C₁₋₆alkyl-C(═O)—NR¹—;    —O—C₁₋₆alkyl-C(═O)—NR¹—; —C₁₋₆alkyl-O—C(═O)—NR¹—; —C₁₋₆alkyl-;    —O—C₁₋₆alkyl-; —C₁₋₆alkyl-O—; —NR¹—C₁₋₆alkyl-; —C₁₋₆alkyl-NR¹—;    —NR¹—C₁₋₆alkyl-NR¹—; —NR¹—C₁₋₆alkyl-C₃₋₇cycloalkyl-; —C₂₋₆alkenyl-;    —C₂₋₆alkynyl-; —O—C₂₋₆alkenyl-; —C₂₋₆alkenyl-O—; —NR¹—C₂₋₆alkenyl-;    —C₂₋₆alkenyl-NR¹—; —NR¹—C₂₋₆alkenyl-NR¹—;    —NR¹—C₂₋₆alkenyl-C₃₋₇cycloalkyl-; —O—C₂₋₆alkynyl-; —C₂₋₆alkynyl-O—;    —NR¹—C₂₋₆alkynyl-; —C₂₋₆alkynyl-NR¹—; —NR¹—C₂₋₆alkynyl-NR¹—;    —NR¹—C₂₋₆alkynyl-C₃₋₇cycloalkyl-; —O—C₁₋₆alkyl-O—;    —O—C₂₋₆alkenyl-O—; —O—C₂₋₆akynyl-O—; —CHOH—; —S—; —S(═O)—; —S(═O)₂—;    —S(═O)—NR¹—; —S(═O)₂—NR¹—; —NR¹—S(═O)—; —NR¹—S(═O)₂—; —S—C₁₋₆alkyl-;    —C₁₋₆alkyl-S—; —S—C₂₋₆alkenyl-; —C₂₋₆alkenyl-S—; —S—C₂₋₆alkynyl-;    —C₂₋₆alkynyl-S—; —O—C₁₋₆alkyl-S(═O)₂— or a direct bond;-   R² is hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, R²⁰, each of    said groups representing R² may optionally be substituted where    possible with one or more substituents each independently being    selected from ═S; ═O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵—O—; SH;    R¹⁵—S—; formyl; carboxyl; R¹⁵—C(═O)—; R¹⁵—O—C(═O)—; R¹⁵—C(═O)—O—;    R¹⁵—O—C(═O)—O—; —SO₃H; R¹⁵—S(═O)—; R¹⁵—S(═O)₂—; R⁵R⁶N;    R⁵R⁶N—C₁₋₆alkyl; R⁵R⁶N—C₃₋₇cycloalkyl; R⁵R⁶N—C₁₋₆alkyloxy;    R⁵R⁶N—C(═O)—; R⁵R⁶N—C(═S)—; R⁵R⁶N—C(═O)—NH—; R⁵R⁶N—C(═S)—NH—;    R⁵R⁶N—S(═O)_(n)—; R⁵R⁶N—S(═O)_(n)—NH—; R¹⁵—C(═S)—; R¹⁵—C(═O)—NH—;    R¹⁵—O—C(═O)—NH—; R¹⁵—S(═O)_(n)—NH—; R¹⁵—O—S(═O)_(n)—NH—;    R¹⁵—C(═S)—NH—; R¹⁵—O—C(═S)—NH—; R¹⁷R¹⁸N—Y_(1a)—;    R¹⁷R¹⁸N—Y₂—NR¹⁶—Y₁—; R¹⁵—Y₂—NR¹⁹—Y₁—; H—Y₂—NR¹⁹—Y₁—;-   R³ is hydrogen; hydroxy; halo; C₁₋₆alkyl; C₁₋₆alkyl substituted with    cyano, hydroxy or —C(═O)R⁷; C₂₋₆akenyl; C₂₋₆alkenyl substituted with    one or more halogen atoms or cyano; C₂₋₆alkynyl; C₂₋₆alkynyl    substituted with one or more halogen atoms or cyano; C₁₋₆alkyloxy;    C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; carboxyl;    cyano; nitro; amino; mono- or di(C₁₋₆alkyl)amino; polyhaloC₁₋₆alkyl;    polyhaloC₁₋₆alkyloxy; polyhaloC₁₋₆alkylthio; R²¹; R²¹—C₁₋₆alkyl;    R²¹—O—; R²¹—S—; R²¹—C(═O)—; R²¹—S(═O)_(p)—; R⁷—S(═O)_(p)—;    R⁷—S(═O)_(p)—NH—; R²¹—S(═O)_(p)—NH—; R⁷—C(═O)—; —NHC(═O)H;    —C(═O)NHNH₂; R⁷—C(═O)—NH—; R²¹—C(═O)—NH—; —C(═NH)R⁷; —C(═NH)R²¹;-   R^(4a) or R^(4b) each independently are hydrogen, R⁸,    —Y₁—NR⁹—Y₂—NR¹⁰R¹¹, —Y₁—NR⁹—Y₁—R⁸, —Y₁—NR⁹R¹⁰;-   R⁵ and R⁶ each independently are hydrogen, R⁸, —Y₁—NR⁹—Y₂—NR¹⁰R¹¹,    —Y₁—NR⁹—Y₁—R⁸, —Y₁—NR⁹R¹⁰;-   R⁷is C₁₋₆alkyl, C₁₋₆alkyloxy, amino, mono- or di(C₁₋₆alkyl)amino or    polyhaloC₁₋₆alkyl;-   R⁸ is C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; a monocyclic, bicyclic or    tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic    partially saturated carbocycle; a monocyclic, bicyclic or tricyclic    aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated    heterocycle; a monocyclic, bicyclic or tricyclic partially saturated    heterocycle; a monocyclic, bicyclic or tricyclic aromatic    heterocycle; C₁₋₆alkyl substituted with a monocyclic, bicyclic or    tricyclic saturated carbocycle or with a monocyclic, bicyclic or    tricyclic partially saturated carbocycle or with a monocyclic,    bicyclic or tricyclic aromatic carbocycle or with a monocyclic,    bicyclic or tricyclic saturated heterocycle or with a monocyclic,    bicyclic or tricyclic partially saturated heterocycle or with a    monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said    groups representing R⁸ may optionally be substituted with one or    more substituents selected from R¹², R¹³ and R¹⁴;-   R⁹, R¹⁰ and R¹¹ each independently are hydrogen or R⁸;-   R¹², R¹³ and R¹⁴ each independently are hydrogen; R¹⁵; hydroxy;    halo; nitro; cyano; R¹⁵—O—; SH; R¹⁵—S—; formyl; carboxyl;    R¹⁵—C(═O)—; R¹⁵—O—C(═O)—; R¹⁵—C(═O)—O—; R¹⁵—O—C(═O)—O—; —SO₃H;    R¹⁵—S(═O)—; R¹⁵—S(═O)₂—; R¹⁵R¹⁶N—S(═O)—; R¹⁵R¹⁶N—S(═O)₂—;    R¹⁷R¹⁸N—Y₁—; R¹⁷R¹⁸N—Y₂—NR¹⁶—Y₁—; R¹⁵—Y₂—NR¹⁹—Y₁—; H—Y₂—NR¹⁹—Y₁—;    oxo;-   R¹⁵ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, a monocyclic, bicyclic    or tricyclic saturated carbocycle; a monocyclic, bicyclic or    tricyclic partially saturated carbocycle; a monocyclic, bicyclic or    tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic    saturated heterocycle; a monocyclic, bicyclic or tricyclic partially    saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic    heterocycle; C₁₋₆alkyl substituted with a monocyclic, bicyclic or    tricyclic saturated carbocycle or with a monocyclic, bicyclic or    tricyclic partially saturated carbocycle or with a monocyclic,    bicyclic or tricyclic aromatic carbocycle or with a monocyclic,    bicyclic or tricyclic saturated heterocycle or with a monocyclic,    bicyclic or tricyclic partially saturated heterocycle or with a    monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said    substituents representing R¹⁵ may optionally be substituted with one    or more substituents selected from R¹², R¹³ and R¹⁴;-   R¹⁶, R¹⁷, R¹⁸ and R¹⁹ each independently are hydrogen or R¹⁵;-   R²⁰ is a monocyclic, bicyclic or tricyclic saturated carbocycle; a    monocyclic, bicyclic or tricyclic partially saturated carbocycle; a    monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic,    bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic    or tricyclic partially saturated heterocycle; a monocyclic, bicyclic    or tricyclic aromatic heterocycle;-   R²¹ is a monocyclic, bicyclic or tricyclic saturated carbocycle; a    monocyclic, bicyclic or tricyclic partially saturated carbocycle; a    monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic,    bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic    or tricyclic partially saturated heterocycle; a monocyclic, bicyclic    or tricyclic aromatic heterocycle, each of said carbocycles or    heterocycles representing R²¹ may optionally be substituted with one    or more substituents selected from R¹², R¹³ and R¹⁴;-   Y_(1a) is —Y₃—S(═O)—Y₄—; —Y₃—S(═O)₂—Y₄—, —Y₃—C(═O)—Y₄—,    —Y₃—C(═S)—Y₄—, Y₃—O—Y₄—, —Y₃—S—Y₄—, —Y₃—O—C(═O)—Y₄— or    —Y₃—C(═O)—O—Y₄—;-   Y₁ or Y₂ each independently are a direct bond, —Y₃—S(═O)—Y₄—;    —Y₃—S(═O)₂—Y₄—, —Y₃—C(═O)—Y₄—, —Y₃—C(═S)—Y₄—, —Y₃—O—Y₄—, —Y₃—S—Y₄—,    —Y₃—O—C(═O)—Y₄— or —Y₃—C(═O)—O—Y₄—;-   Y₃ or Y₄ each independently are a direct bond, C₁₋₆alkanediyl,    C₂₋₆alkenediyl or C₂₋₆alkynediyl;-   n is 1 or 2;-   m is 1 or 2;-   p is 1 or 2;-   r is 1 to 5;-   s is 1 to 3;-   aryl is phenyl or phenyl substituted with one, two, three, four or    five substituents each independently selected from halo, C₁₋₆alkyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl and    polyhaloC₁₋₆alkyloxy;-   provided that —X—R and/or R³is other than hydrogen; and-   provided that the following compounds-   N-methoxy-N-methyl-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinecarboxamide    and    N-phenyl-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinecarboxamide    are not included.

Further particular compounds are those compounds of formula (I) or (I′)wherein ring A is pyrimidinyl, pyrazinyl or pyridazinyl, in particularpyrimidinyl, and wherein R³ is other than C₁₋₆alkyloxy orpolyhaloC₁₋₆alkyloxy.

Yet further particular compounds are those compounds of formula (I) or(I′) wherein

-   ring A is pyrimidinyl, pyrazinyl or pyridazinyl, in particular    pyrimidinyl;-   R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;    C₁₋₆alkyloxyC₁₋₆alkylcarbonyl optionally substituted with    C₁₋₆alkyloxycarbonyl;-   X is —NR¹—; —C(═O)—; —O—C(═O)—; —C(═O)—O—; —O—C(═O)—C₁₋₆alkyl-;    —C(═O)—O—C₁₋₆alkyl-; —O—C₁₋₆alkyl-C(═O)—; —C(═O)—C₁₋₆alkyl-O—;    —O—C(═O)—NR¹—; —NR¹—C(═O)—O—; —C(═O)—NR¹—, —NR¹—C(═O)—; —C₁₋₆alkyl-;    —O—C₁₋₆alkyl-; —C₁₋₆alkyl-O—; —NR¹—C₁₋₆alkyl-; —C₁₋₆alkyl-NR¹—;    —NR¹—C₁₋₆alkyl-NR¹—; —C₂₋₆alkenyl-; —C₂₋₆alkynyl-; —O—C₂₋₆alkenyl-;    —C₂₋₆alkenyl-O—; —NR¹—C₂₋₆alkenyl-; —C₂₋₆alkenyl-NR¹—;    —NR¹—C₂₋₆alkenyl-NR¹—; —O—C₂₋₆alkynyl-; —C₂₋₆alkynyl-O—;    —NR¹—C₂₋₆alkynyl-; —C₂₋₆alkynyl-NR¹—; —NR¹—C₂₋₆alkynyl-NR¹—;    —O—C₁₋₆alkyl-O—; —O—C₂₋₆alkenyl-O—; —O—C₂₋₆alkynyl-O—; —CHOH—;    —S(═O)—; —S(═O)₂—; —S(═O)—NR¹—; —S(═O)₂—NR¹—; —NR¹—S(═O)—;    —NR¹—S(═O)₂—; —S—C₁₋₆alkyl-; —C₁₋₆alkyl-S—; —S—C₂₋₆alkenyl-;    —C₂₋₆alkenyl-S—; —S—C₂₋₆alkynyl-; —C₂₋₆alkynyl-S—;-   R² is hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, R²⁰, each of    said groups representing R² may optionally be substituted where    possible with one or more substituents each independently being    selected from ═O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵—O—; SH;    R¹⁵—S—; fornyl; carboxyl; R¹⁵—C(═O)—; R¹⁵—O—C(═O)—; R¹⁵—C(═O)—O—;    R¹⁵—O—C(═O)—O—; —SO₃H; R¹⁵—S(═O)—; R¹⁵—S(═O)₂—; R⁵R⁶N;    R⁵R⁶N—C₁₋₆alkyl; R⁵R⁶N—C₁₋₆alkyloxy; R⁵R⁶N—C(═O)—; R⁵R⁶N—S(═O)_(n)—;    R⁵R⁶N—S(═O)_(n)—NH—; R¹⁵—C(═O)—NH—;-   R³ is hydroxy; halo; C₁₋₆alkyl substituted with cyano, hydroxy or    —C(═O)R⁷; C₂₋₆alkenyl; C₂₋₆alkenyl substituted with one or more    halogen atoms or cyano; C₂₋₆alkynyl; C₂₋₆alkynyl substituted with    one or more halogen atoms or cyano; C₁₋₆alkylthio;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; carboxyl; cyano; nitro;    amino; mono- or di(C₁₋₆alkyl)amino; polyhaloC₁₋₆alkyl;    polyhaloC₁₋₆alkylthio; R²¹; R²¹—C₁₋₆alkyl; R —O—; R²¹—S—;    R²¹—C(═O)—; R²¹—S(═O)_(p)—; R⁷—S(═O)_(p)—; R⁷—C(═O)—; —NHC(═O)H;    —C(═O)NHNH₂; R⁷—C(═O)—NH—; R²¹—C(═O)—NH—; —C(═NH)R⁷; —C(═NH)R²¹;-   R^(4a) or R^(4b) each independently are hydrogen or R⁸;-   R⁵ and R⁶ each independently are hydrogen or R⁸;-   R⁷is C₁₋₆alkyl, C₁₋₆alkyloxy, amino, mono- or di(C₁₋₆alkyl)amino or    polyhaloC₁₋₆alkyl;-   R⁸ is C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; a monocyclic, bicyclic or    tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic    partially saturated carbocycle; a monocyclic, bicyclic or tricyclic    aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated    heterocycle; a monocyclic, bicyclic or tricyclic partially saturated    heterocycle; a monocyclic, bicyclic or tricyclic aromatic    heterocycle; C₁₋₆alkyl substituted with a monocyclic, bicyclic or    tricyclic saturated carbocycle or with a monocyclic, bicyclic or    tricyclic partially saturated carbocycle or with a monocyclic,    bicyclic or tricyclic aromatic carbocycle or with a monocyclic,    bicyclic or tricyclic saturated heterocycle or with a monocyclic,    bicyclic or tricyclic partially saturated heterocycle or with a    monocyclic, bicyclic or tricyclic aromatic heterocycle;-   R¹², R¹³ and R¹⁴ each independently are hydrogen; R¹⁵; hydroxy;    halo; nitro; cyano; R¹⁵—O—; SH; R¹⁵—S—; formyl; carboxyl;    R¹⁵—C(═O)—; R¹⁵—O—C(═O)—; R¹⁵—C(═O)—O—; R¹⁵—O—C(═O)—O—; —SO₃H;    R¹⁵—S(═O)—; R¹⁵—S(═O)₂—; R¹⁵R¹⁶N—S(═O)—; R¹⁵R¹⁶N—S(═O)₂—;-   R¹⁵ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, a monocyclic, bicyclic    or tricyclic saturated carbocycle; a monocyclic, bicyclic or    tricyclic partially saturated carbocycle; a monocyclic, bicyclic or    tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic    saturated heterocycle; a monocyclic, bicyclic or tricyclic partially    saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic    heterocycle; C₁₋₆alkyl substituted with a monocyclic, bicyclic or    tricyclic saturated carbocycle or with a monocyclic, bicyclic or    tricyclic partially saturated carbocycle or with a monocyclic,    bicyclic or tricyclic aromatic carbocycle or with a monocyclic,    bicyclic or tricyclic saturated heterocycle or with a monocyclic,    bicyclic or tricyclic partially saturated heterocycle or with a    monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said    substituents representing R¹⁵ may optionally be substituted with one    or more substituents selected from R¹², R¹³ and R¹⁴;-   R¹⁶ is hydrogen or R¹⁵;-   R²⁰ is a monocyclic, bicyclic or tricyclic saturated carbocycle; a    monocyclic, bicyclic or tricyclic partially saturated carbocycle; a    monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic,    bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic    or tricyclic partially saturated heterocycle; a monocyclic, bicyclic    or tricyclic aromatic heterocycle;-   R²¹ is a monocyclic, bicyclic or tricyclic saturated carbocycle; a    monocyclic, bicyclic or tricyclic partially saturated carbocycle; a    monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic,    bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic    or tricyclic partially saturated heterocycle; a monocyclic, bicyclic    or tricyclic aromatic heterocycle, each of said carbocycles or    heterocycles representing R²¹ may optionally be substituted with one    or more substituents selected from R¹², R¹³ and R¹⁴;-   n is 1 or 2;-   m is 1 or 2;-   p is 1 or 2;-   s is 1 to 3;-   aryl is phenyl or phenyl substituted with one, two, three, four or    five substituents each independently selected from halo, C₁₋₆alkyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl and    polyhaloC₁₋₆alkyloxy.

Further interesting compounds are those compounds of formula (I) or (I′)as defined hereinabove wherein

-   Z represents O;-   ring A is pyridyl or pyrimidinyl;-   R¹ is hydrogen;-   X is —O—; —O—C(═O)—NR¹—; —O—C₁₋₆alkyl-; —O—C₂₋₆alkenyl-;    —O—C₁₋₆alkyl-O— or a direct bond;-   R² is hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, R²⁰, each of said groups    representing R² may optionally be substituted where possible with    one or more substituents each independently being selected from R¹⁵;    halo; nitro; cyano; R¹⁵—O—; R⁵R⁶N; R⁵R⁶N—S(═O)_(n)—NH—;-   R³ is hydrogen or cyano;-   R^(4a) or R^(4b) each independently are hydrogen or R⁸;-   R⁵ and R⁶ each independently are hydrogen or R⁵;-   R⁸ is C₁₋₆alkyl;-   R¹², R¹³ and R¹⁴ each independently are hydrogen; R¹⁵; halo; nitro;    cyano; R¹⁷R¹⁸N—Y₁—;-   R¹⁵ is C₁₋₆alkyl, a monocyclic, bicyclic or tricyclic aromatic    carbocycle; a monocyclic, bicyclic or tricyclic saturated    heterocycle; a monocyclic, bicyclic or tricyclic partially saturated    heterocycle; a monocyclic, bicyclic or tricyclic aromatic    heterocycle; each of said substituents representing R¹⁵ may    optionally be substituted with one or more substituents selected    from R¹², R¹³ and R¹⁴;-   R¹⁸ and R¹⁹ are hydrogen;-   R²⁰ is a monocyclic, bicyclic or tricyclic aromatic carbocycle; a    monocyclic, bicyclic or tricyclic saturated heterocycle; a    monocyclic, bicyclic or tricyclic partially saturated heterocycle; a    monocyclic, bicyclic or tricyclic aromatic heterocycle;-   Y₁ is a direct bond;-   n is 1 or 2;-   s is 1;-   provided that —X—R² and/or R³ is other than hydrogen.

Yet further interesting compounds are those compounds of formula (I) or(I′) as defined hereinabove provided that the compound is other than

Z is as defined hereinabove; X is O; R² is C₁₋₁₀alkyl, C₂₋₁₀alkenyl orC₂₋₁₀alkynyl, said groups representing R² may optionally be substituted;R^(3a) is C₁₋₆alkyloxy; R^(3b) is hydrogen, halo, optionally substitutedC₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl, optionally substitutedC₂₋₁₀alkynyl, hydroxy, amino, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyl-C(═O)—NH—, C₁₋₆alkyloxy, polyhaloC₁₋₆alkyloxy, C₁₋₆alkylthio,polyhaloC₁₋₆alkylthio, aryloxy; R¹ is hydrogen or C₁₋₆alkyl; R^(4a) andR^(4b) are each independently hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl, C₃₋₁₀heterocycloalkyl,C₃₋₁₀heterocycloalkenyl, a C₆₋₁₄aromatic group, a C₅₋₁₄heteroaromaticgroup, each of said groups representing R^(4a) and R^(4b) may optionallybe substituted;

wherein Z, ring A, R^(4a) and R^(4b), R², R³ and s are as definedhereinabove; R¹ is hydrogen; aryl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;C₁₋₆alkyloxyC₁₋₆alkylcarbonyl optionally substituted withC₁₋₆alkyloxycarbonyl; X is a direct bond or C₁₋₆alkyl.

Further preferred compounds are those compounds of formula (I) or (I′)wherein one or where possible more of the following restrictions apply:

-   a) X is a direct bond and R² is hydrogen;-   b) R² and R³ are other than hydrogen;-   c) R³ is hydrogen;-   d) when s is 1 and said R³ substituent is placed at the para    position compared to the NR¹ linker then said R³ substituent is    other than C₁₋₆alkyloxy or polyhaloC₁₋₆alkyloxy;-   e) X is other than a direct bond or C₁₋₆alkyl;-   f) both X—R² and R³ are other than hydrogen.

Also preferred are those compounds of formula (I) or (I′) wherein thecompounds are compounds selected from one of the following formulae:

wherein R³ is suitably hydrogen; hydroxy; halo; C₁₋₆alkyl; C₁₋₆alkylsubstituted with cyano, hydroxy or —C(═O)R⁷; C₂₋₆alkenyl; C₂₋₆alkenylsubstituted with one or more halogen atoms or cyano; C₂₋₆alkynyl;C₂₋₆alkynyl substituted with one or more halogen atoms or cyano;C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; carboxyl;cyano; nitro; amino; mono- or di(C₁₋₆alkyl)amino; polyhaloC₁₋₆alkyl;polyhaloC₁₋₆alkylthio; R²¹; R²¹—C₁₋₆alkyl; R²¹—O—; R²¹—S—; R²¹—C(═O)—;R²¹—S(═O)_(p)—; R⁷—S(═O)_(p)—; R⁷—S(═O)_(p)—NH—; R²¹—S(═O)_(p)—NH—;R⁷—C(═O)—; —NHC(═O)H; —C(═O)NHNH₂; R⁷—C(═O)—NH—; R²¹—C(═O)—NH—;—C(═NH)R⁷; —C(═NH)R²¹;

Also preferred are those compounds of formula (a-1) wherein one or more,preferably all of the following restrictions apply

-   (a) s is 1 and said R³ substituent is placed at the para position    compared to the NR¹ linker;-   (b) X is other than a direct bond or C₁₋₆alkyl.

Particular preferred compounds of formula (I) or (I′) are thosecompounds selected from

-   2-[[4-cyano-3-[[(dimethylamino)sulfonyl]amino]phenyl]methoxy]phenyl]amino)-4-pyrimidinecarboxamide    (compound 8);-   2-[[4-cyano-3-[(2-quinolinylmethoxy)phenyl]amino]-4-pyrimidinecarboxamide    (compound 21);-   2-[[4-cyano-3-[2-(4-fluorophenoxy)propoxy]phenyl]amino]-4-pyrimidinecarboxamide    (compound 16);-   2-[[4-cyano-3-[(2-methoxyphenyl)methoxy]phenyl]amino]-4-pyrimidinecarboxamide    compound 30);-   2-[[4-cyano-3-[(1-ethyl-1H-imidazol-2-yl)methoxy]phenyl]amino-4-pyrimidinecarboxamide    compound 24);-   2-[[4-cyano-3-(phenylmethoxy)phenyl]amino]-4-pyrimidinecarboxamide    (compound 2);-   2-[[4-cyano-3-[(4-methoxyphenyl)methoxy]phenyl]amino]-4-pyrimidinecarboxamide    (compound 13);-   2-[[4-cyano-3-(2-naphthalenylmethoxy)phenyl]amino]-4-pyrimidinecarboxamide    (compound 38);-   a N-oxide, a pharmaceutically acceptable addition salt, a quatemary    amine and a stereochemically isomeric form thereof.

Other particular preferred compounds of formula (I) or (I′) are thosecompounds selected from

-   2-(3-benzyloxy-4-cyano-phenylamino)-nicotinamide;-   6-(3-benzyloxy-4-cyano-phenylamino)-nicotinamide;-   4-(3-benzyloxy-4-cyano-phenylamino)-pyridine-2-carboxylic acid    amide;-   2-(3-benzyloxy-4-cyano-phenylamino)-isonicotinamide;-   a N-oxide, a pharmaceutically acceptable addition salt, a quaternary    amine and a stereochemically isomeric form thereof.

Compounds of formula (I) can be prepared by reacting an intermediate offormula (II) with an intermediate of formula (III) wherein W₁ representsa suitable leaving group, such as for example a halo atom, e.g. chloro,bromo, or C₁₋₆alkyl-S—, in the presence of a suitable solvent, such asfor example N,N-dimethylacetamide, N,N-dimethylformamide, methylenechloride, (CH₃OCH₂CH₂)₂O, tetrahydrofuran, water, an alcohol, e.g.ethanol, isopropanol and the like, and optionally in the presence of asuitable acid, such as for example hydrochloric acid, or a suitablebase, such as for example sodium carbonate, N,N-diethylethanamine orN,N-diisopropylethanamine.

Compounds of formula (I) can also be prepared by reacting anintermediate of formula (IV) wherein W₂ represents a suitable leavinggroup, such as for example a halo atom, e.g. chloro, bromo and the like,with an intermediate of formula (V) optionally in the presence of asuitable solvent, such as for example CH₃OCH₂CH₂OH.

Compounds of formula (I) wherein Z is O, said compounds beingrepresented by formula (I-a), can be prepared by reacting anintermediate of formula (VI) wherein W₃ represents a suitable leavinggroup, such as for example a halo atom, e.g. chloro, bromo and the like,or C₁₋₆alkyloxy, with an intermediate of formula (VII) in the presenceof a suitable solvent, such as for example tetrahydrofuran or analcohol, e.g. methanol, ethanol and the like.

Compounds of formula (I) wherein Z is O and R^(4a) and R^(4b) arehydrogen, said compounds being represented by formula (I-a-1), can beprepared by reacting an intermediate of formula (VIII) with a suitableoxidizing agent, such as for example H₂O₂ or NaBO₃, in the presence of asuitable solvent, such as for example water, dimethylsulfoxide or analcohol, e.g. methanol, ethanol and the like, and optionally in thepresence of a suitable base, such as for example dipotassium carbonate.

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, distillation, trituration andchromatography.

The compounds of formula (I) may further be prepared by convertingcompounds of formula (I) into each other according to art-known grouptransformation reactions.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.t.butyl hydro-peroxide. Suitable solvents are, for example, water, loweralcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Compounds of formula (I) wherein R³ is halo, or wherein R² issubstituted with halo, can be converted into a compound of formula (I)wherein R³ is cyano, or wherein R² is substituted with cyano, byreaction with a suitable cyano-introducing agent, such as sodium cyanideor CuCN, optionally in the presence of a suitable catalyst, such as forexample tetrakis(triphenylphosphine)palladium and a suitable solvent,such as N,N-dimethylacetamide or N,N-dimethylformamide. A compound offormula (I) wherein R³ is cyano, or wherein R² is substituted withcyano, can further be converted into a compound of formula (I) whereinR³ is aminocarbonyl, or wherein R² is substituted with aminocarbonyl, byreaction with HCOOH, in the presence of a suitable acid, such ashydrochloric acid. A compound of formula (I) wherein R³ is cyano, orwherein R² is substituted with cyano, can also further be converted intoa compound of formula (I) wherein R³ is tetrazolyl, or wherein R² issubstituted with tetrazolyl, by reaction with sodium azide in thepresence of ammonium chloride and N,N-dimethylacetoacetamide.

Compounds of formula (I) wherein R² is substituted with halo can also beconverted into a compound of formula (I) wherein R² is substituted withmercapto, byreaction with disodium sulfide in the presence of a suitablesolvent, such as, for example, 1,4-dioxane.

Compounds of formula (I) wherein R² is substituted with halo, can alsobe converted into a compound of formula (I) wherein R² is substitutedwith C₁₋₆alkylthio, by reaction with a reagent of formula alkalinemetal⁺⁻S—C₁₋₆alkyl, e.g. Na⁺⁻S—C₁₋₆alkyl, in the presence of a suitablesolvent, such as dimethylsulfoxide. The latter compounds can further beconverted into a compound of formula (I) wherein R² is substituted withC₁₋₆alkyl-S(═O)—, by reaction with a suitable oxidizing agent, such as aperoxide, e.g. 3-chlorobenzenecarboperoxoic acid, in the presence of asuitable solvent, such as an alcohol, e.g. ethanol.

Compounds of formula (I) wherein R³ is halo, or wherein R² issubstituted with halo, can also be converted into a compound of formula(I) wherein R³ is C₁₋₆alkyloxy, or wherein R² is substituted withC₁₋₆alkyloxy, by reaction with an alcoholate salt, such as, for example,LiOC₁₋₆alkyl, in the presence of a suitable solvent, such as an alcohol,e.g. methanol.

Compounds of formula (I) wherein R³ is halo, or wherein R² issubstituted with halo, can also be converted into a compound of formula(I) wherein R³ is hydroxy, or wherein R² is substituted with hydroxy, byreaction with a suitable carboxylate, e.g. sodium acetate, in a suitablereaction-inert solvent, such as, for example, dimethylsulfoxide,followed by treating the obtained reaction product with a suitable base,such as pyridine, and acetyl chloride.

Compounds of formula (I) wherein R³ is halo, or wherein R² issubstituted with halo, can also be converted into a compound of formula(I) wherein R³ is a monocyclic, bicyclic or tricyclic saturatedcarbocycle; a monocyclic, bicyclic or tricyclic partially saturatedcarbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; amonocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic,bicyclic or tricyclic partially saturated heterocycle; a monocyclic,bicyclic or tricyclic aromatic heterocycle, or wherein R² is substitutedwith a monocyclic, bicyclic or tricyclic saturated carbocycle; amonocyclic, bicyclic or tricyclic partially saturated carbocycle; amonocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic,bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic ortricyclic partially saturated heterocycle; a monocyclic, bicyclic ortricyclic aromatic heterocycle, said substituents being represented by-L, by reaction with -L in the presence of a suitable base, such as forexample sodium hydroxide, dipotassium carbonate, sodium hydride, in thepresence of a suitable solvent, such as, for example, 1,4-dioxane,N,N-dimethylacetamide, N,N-dimethylformamide.

Compounds of formula (I) wherein R³ is chloro, or wherein R² issubstituted with chloro, can be converted into a compound of formula (I)wherein R³ is fluoro, or wherein R² is substituted with fluoro, byreaction with a suitable fluoride salt, such as for example potassiumfluoride, in the presence of a suitable solvent, e.g. sulfolane.

Compounds of formula (I) wherein X—R² is hydrogen and wherein the R³substituent positioned at the meta position compared to the NR¹ linker,is halo, can be converted into a compound of formula (I) wherein said R³substituent is replaced by X—R² wherein X is other than a direct bondwhen R² is hydrogen, by reaction with H—X—R² in the presence of asuitable solvent, such as N,N-dimethylacetamide or N,N-dimethylformamideoptionally in the presence of a suitable base, such as for exampleN,N-diisopropylethanamine.

Compounds of formula (I) wherein R² is substituted withC₁₋₄alkyloxyC₁₋₆alkyl, can be converted into a compound of formula (I)wherein R² is substituted with hydroxyC₁₋₆alkyl, by dealkylating theether in the presence of a suitable dealkylating agent, such as, forexample, tribromoborane, and a suitable solvent, such as methylenechloride.

Compounds of formula (I) wherein R³ or X—R² are C₁₋₆alkyloxycarbonyl, orwherein R² is substituted with C₁₋₆alkyloxycarbonyl, can be convertedinto a compound of formula (I) wherein R³ or X—R² are aminocarbonyl, orwherein R² is substituted with aminocarbonyl or mono- ordi(C₁₋₆alkyl)aminocarbonyl by reaction with a suitable agent such asammonia, NH₂(C₁₋₆alkyl), AlCH₃[N(C₁₋₆alkyl)₂]Cl optionally in thepresence of a suitable acid, such as for example hydrochloric acid, andin the presence of a suitable solvent such as an alcohol, e.g. methanol;tetrahydrofuran; N,N-diisopropylethane.

Compounds of formula (I) wherein R³ is hydrogen or wherein R² isunsubstituted, can be converted into a compound wherein R³ is halo orwherein R² is substituted with halo, by reaction with a suitablehalogenating agent, such as, for example Br₂ or1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2,2,2]octanebis[tetrafluoroborate], in the presence of a suitable solvent, such astetrahydrofuran, water, acetonitrile, chloroform and optionally in thepresence of a suitable base such as N,N-diethylethanamine.

Compounds of formula (I) wherein R³ or —X—R² are C₁₋₆alkyloxycarbonyl orwherein R² is substituted with C₁₋₆alkyloxycarbonyl, can be convertedinto a compound of formula (I) wherein R³ or X—R² are hydroxymethyl orwherein R² is substituted with hydroxymethyl by reaction with a suitablereducing agent, such as for example LiAlH₄.

Compounds of formula (I) wherein —X—R² is —O—CH₂-(optionallysubstituted)phenyl may be converted into a compound of formula (I)wherein —X—R² represents OH by reaction with a suitable reducing agent,such as H₂, in the presence of a suitable catalyst, such as for examplepalladium on charcoal, and a suitable solvent, such as for example analcohol, e.g. methanol, ethanol and the like, or N,N-dimethylacetamide.Compounds of formula (I) wherein —X—R² represents OH may be convertedinto a compound of formula (I) wherein —X—R² represents —O—X₁—R² byreaction with W₁—X₁—R² wherein W₁ represents a suitable leaving group,such as for example a halo atom, e.g. chloro, and wherein —O—X₁represents those linkers falling under the definition of X which areattached to the phenyl ring via a O atom (in said definition X₁represents that part of the linker wherein the O atom is not included),in the presence of a suitable base, such as for example dipotassiumcarbonate, and a suitable solvent, such as for exampleN,N-dimethylacetamide.

Compounds of formula (I) wherein R³ is nitro, or wherein R² issubstituted with nitro, may be converted into a compound of formula (I)wherein R³ is amino or wherein R² is substituted with amino, by reactionwith a suitable reducing agent, such as for example H₂, in the presenceof a suitable catalyst, such as for example palladium on charcoal, asuitable catalyst poison, such as for example a thiophene solution, anda suitable solvent, such as for example an alcohol, e.g. methanol,ethanol and the like.

Compounds of formula (I) wherein R² is substituted with NH₂, can beconverted into a compound of formula (I) wherein R is substituted withNH—S(═O)₂—NR⁵R⁶, by reaction with W₁—S(═O)₂—NR⁵R⁶ wherein W₁ representsa suitable leaving group such as for example a halo atom, e.g. chloro,in the presence of a suitable solvent, such as for exampleN,N-dimethylacetamide and a suitable base, such as for exampleN,N-diethylethanamine.

Some of the compounds of formula (I) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Some of the intermediates and starting materials are known compounds andmay be commercially available or may be prepared according to art-knownprocedures, such as those described in WO 99/50250, WO 00/27825 or EP0,834,507.

Intermediates of formula (III) can be prepared by reacting anintermediate of formula (IX) wherein W₁ is as defined hereinabove, withan intermediate of formula (X) in the presence of a suitable solvent,such as for example acetonitrile or dioxane, and in the presence of asuitable base, such as for example N,N-diisopropylethanamine.

Intermediates of formula (VI) can be prepared by reacting anintermediate of formula (V) with an intermediate of formula (XI) whereinW₄ represents a suitable leaving group, such as for example a halo atom,e.g. chloro and the like, in the presence of a suitable solvent, such asfor example CH₃OCH₂CH₂OH.

Intermediates of formula (VI) wherein R¹ is hydrogen, said intermediatesbeing represented by formula (VI-a), can be prepared by reacting anintermediate of formula (XI) with an intermediate of formula (XII) inthe presence of a suitable salt such as for example dipotassiumcarbonate and CuI.

Intermediates of formula (XII) can be prepared by reacting anintermediate of formula (Y) wherein R¹ is hydrogen, said intermediatebeing represented by formula (V-a), with formic acid.

Intermediates of formula (VI) wherein X—R² is OH, said intermediatesbeing represented by formula (VI-b), can be prepared by reducing anintermediate of formula (XIII) in the presence of a suitable reducingagent, such as for example H₂, a suitable catalyst, such as palladium oncharcoal, and a suitable solvent, such as an alcohol, e.g. ethanol andthe like.

Intermediates of formula (VI) wherein ring A is pyrimidine with the NR¹linker in position 2 and W₃ represents an alcoholate, i.e. C₁₋₆alkyl,said intermediates being represented by formula (VI-c), can be preparedby reacting an intermediate of formula (XIV) with an intermediate offormula (XV) in the presence of a suitable solvent, such as for exampleN,N-dimethylacetamide, optionally in the presence of a suitablealcoholate, such as for example sodium ethanolate.

Intermediates of formula (XV) can be prepared by reacting anintermediate of formula (XVI) with 1,1-diethoxy-N,N-dimethylmethanamine.

Intermediates of formula (XIV) can be prepared by reacting anintermediate of formula (V) with cyanamide in the presence of a suitablesolvent, such as for example diglyme.

Intermediates of formula (VIII) can be prepared by reacting anintermediate of formula (III) with an intermediate of formula (XVII) inthe presence of a suitable solvent, such as for example dioxane anddiethylether, and a suitable acid, such as for example hydrochloricacid.

Intermediates of formula (VIII) wherein X is —O—C₁₋₆alkyl, saidintermediates being represented by formula (VIII-a), can be prepared byreacting an intermediate of formula (XVIII) wherein W₅ represents asuitable leaving group such as for example a halo atom, e.g. chloro orbromo and the like, with an intermediate of formula (XIX) in thepresence of sodium hydride, and a suitable solvent, such as for exampletetrahydrofuran.

The compounds of formula (I) or (I′) inhibit Glycogen synthase kinase 3(GSK3), in particular glycogen synthase kinase 3 beta (GSK3β). They areselective Glycogen synthase kinase 3 inhibitors. Specific inhibitorycompounds are superior therapeutic agents since they are characterizedby a greater efficacy and lower toxicity by virtue of their specificity.

Synonyms for GSK3 are tau protein kinase I (TPK I), FA (Factor A)kinase, kinase FA and ATP-citrate lysase kinase (ACLK).

Glycogen synthase kinase 3 (GSK3), which exists in two isoforms, i.e.GSK3α and GSK3β, is a proline-directed serine/threonine kinaseoriginally identified as an enzyme that phosphorylates glycogensynthase. However, it has been demonstrated that GSK3 phosphorylatesnumerous proteins in vitro such as glycogen synthase, phosphataseinhibitor I-2, the type-II subunit of cAMP-dependent protein kinase, theG-subunit of phosphatase-1, ATP-citrate lyase, acetyl coenzyme Acarboxylase, myelin basic protein, a microtubule-associated protein, aneurofilament protein, an N-CAM cell adhesion molecule, nerve growthfactor receptor, c-Jun transcription factor, JunD transcription factor,c-Myb transcription factor, c-Myc transcription factor, L-Myctranscription factor, adenomatous polyposis coli tumor supressorprotein, tau protein and β-catenin.

The above-indicated diversity of proteins which may be phosphorylated byGSK3 implies that GSK3 is implicated in numerous metabolic andregulatory processes in cells.

GSK3 inhibitors may therefore be useful in the prevention or treatmentof diseases mediated through GSK3 activity such as bipolar disorder (inparticular manic depression), diabetes, Alzheimer's disease, leukopenia,FTDP-17 (Fronto-temporal dementia associated with Parkinson's disease),cortico-basal degeneration, progressive supranuclear palsy, multiplesystem atrophy, Pick's disease, Niemann Pick's disease type C, DementiaPugilistica, dementia with tangles only, dementia with tangles andcalcification, Down syndrome, myotonic dystrophy, Parkinsonism-dementiacomplex of Guam, aids related dementia, Postencephalic Parkinsonism,prion diseases with tangles, subacute sclerosing panencephalitis,frontal lobe degeneration (FLD), argyrophilic grains disease, subacutesclerotizing panencephalitis (SSPE) (late complication of viralinfections in the central nervous system), inflammatory diseases,cancer, dermatological disorders such as baldness, neuronal damage,schizophrenia, pain, in particular neuropathic pain. GSK3 inhibitors canalso be used to inhibit sperm motility and can therefore be used as malecontraceptives.

In particular, the compounds of the present invention are useful in theprevention or treatment of Alzheimer's disease, diabetes, especiallytype 2 diabetes (non insulin dependent diabetes).

The major neuropathological landmarks in Alzheimer's disease areneuronal loss, the deposition of amyloid fibers and paired helicalfilaments (PHF) or neurofibrillary tangles (NFT). Tangle formationappears to be the consequence of accumulation of aberrantlyphosphorylated tau protein. This aberrant phosphorylation destabilizesneuronal cytoskeleton, which leads to reduced axonal transport,deficient functioning and ultimately neuronal death. The density ofneurofibrillary tangles has been shown to parallel duration and severityof Alzheimer's disease. Reduction of the degree of tau phosphorylationcan provide for neuroprotection and can prevent or treat Alzheimer'sdisease or can slow the progression of the disease. As mentionedhereinabove, GSK3 phosphorylates tau protein. Thus compounds having aninhibitory activity for GSK3 may be useful for the prevention or thetreatment of Alzheimer's disease.

Insulin regulates the synthesis of the storage polysaccharide glycogen.The rate-limiting step in the glycogen synthesis is catalyzed by theenzym glycogen synthase. It is believed that glycogen synthase isinhibited by phosphorylation and that insulin stimulates glycogensynthase by causing a net decrease in the phosphorylation of this enzym.Thus, in order to activate glycogen synthase, insulin must eitheractivate phosphatases or inhibit kinases, or both.

It is believed that glycogen synthase is a substrate for glycogensynthase kinase 3 and that insulin inactivates GSK3 thereby promotingthe dephosphorylation of glycogen synthase.

In addition to the role of GSK3 in insulin-induced glycogen synthesis,GSK3 may also play a role in insulin resistance. It is believed thatGSK3 dependent Insulin Receptor Substrate-1 phosphorylation contributesto insulin resistance.

Therefore, GSK3 inhibition may result in the increased deposition ofglycogen and a concomitant reduction of blood glucose, thus mimicing thehypoglycemic effect of insulin. GSK3 inhibition provides an alternativetherapy to manage insulin resistance commonly observed in non insulindependent diabetes mellitus and obesity. GSK3 inhibitors may thusprovide a novel modality for the treatment of type 1 and type 2diabetes.

GSK3 inhibitors, in particular GSK3β inhibitors, may also be indicatedfor use in the prevention or the treatment of pain, in particularneuropathic pain.

After axotomy or chronic constriction injury, neuronal cells die throughan apoptotic pathway and the morphological changes correlate with theonset of hyperalgesia and/or allodynia.

The induction of apoptosis is probably triggered by a reduced supply ofneurotrophic factors as the time course of neuronal loss is positivelyaltered by administration of neurotrophins. GSK, in particular GSK3β,has been shown to be involved in the initiation of the apoptotic cascadeand trophic factor withdrawal stimulates the GSK3β apoptosis pathway.

In view of the above, GSK3β inhibitors might reduce signals of and evenprevent levels of neuropathic pain.

Due to their GSK3 inhibitory properties, particularly their GSK3βinhibitory properties, the compounds of formula (I) or (I′), theirN-oxides, pharmaceutically acceptable addition salts, quaternary aminesand stereochemically isomeric forms thereof, are useful to prevent ortreat GSK3 mediated diseases, in particular GSK3β mediated diseases,such as bipolar disorder (in particular manic depression), diabetes,Alzheimer's disease, leukopenia, FTDP-17 (Fronto-temporal dementiaassociated with Parkinson's disease), cortico-basal degeneration,progressive supranuclear palsy, multiple system atrophy, Pick's disease,Niemann Pick's disease type C, Dementia Pugilistica, dementia withtangles only, dementia with tangles and calcification, Down syndrome,myotonic dystrophy, Parkinsonism-dementia complex of Guam, aids relateddementia, Postencephalic Parkinsonism, prion diseases with tangles,subacute sclerosing panencephalitis, frontal lobe degeneration (FLD),argyrophilic grains disease, subacute scierotizing panencephalitis(SSPE) (late complication of viral infections in the central nervoussystem), inflammatory diseases, cancer, dermatological disorders such asbaldness, neuronal damage, schizophrenia, pain, in particularneuropathic pain. The present compounds are also useful as malecontraceptives. In general, the compounds of the present invention maybe useful in the treatment of warm-blooded animals suffering fromdisease mediated through GSK3, in particular GSK3β, or they may beuseful to prevent warm-blooded animals to suffer from disease mediatedthrough GSK3, in particular GSK3β. More in particular, the compounds ofthe present invention may be useful in the treatment of warm-bloodedanimals suffering from Alzheimer's disease, diabetes, especially type 2diabetes, cancer, inflammatory diseases or bipolar disorder.

In view of the above described pharmacological properties, the compoundsof formula (I) or any subgroup thereof, their N-oxides, pharmaceuticallyacceptable addition salts, quaternary amines and stereochemicallyisomeric forms, may be used as a medicine. In particular, the presentcompounds can be used for the manufacture of a medicament for treatingor preventing diseases mediated through GSK3, in particular GSK3β. Morein particular, the present compounds can be used for the manufacture ofa medicament for treating or preventing Alzheimer's disease, diabetes,especially type 2 diabetes, cancer, inflammatory diseases or bipolardisorder.

In view of the utility of the compounds of formula (I) or (I′), there isprovided a method of treating warm-blooded animals, including humans,suffering from or a method of preventing warm-blooded animals, includinghumans, to suffer from diseases mediated through GSK3, in particularGSK3β, more in particular a method of treating or preventing Alzheimer'sdisease, diabetes, especially type 2 diabetes, cancer, inflammatorydiseases or bipolar disorder. Said method comprises the administration,preferably oral administration, of an effective amount of a compound offormula (I) or (I′), a N-oxide form, a pharmaceutically acceptableaddition salt, a quaternary amine or a possible stereoisomeric formthereof, to warm-blooded animals, including humans.

The present invention also provides compositions for preventing ortreating diseases mediated through GSK3, in particular GSK3β, comprisinga therapeutically effective amount of a compound of formula (I) or (I′)and a pharmaceutically acceptable carrier or diluent.

The compounds of the present invention or any subgroup thereof may beformulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment. Thecompounds of the present invention may also be administered viainhalation or insufflation by means of methods and formulations employedin the art for administration via this way. Thus, in general thecompounds of the present invention may be administered to the lungs inthe form of a solution, a suspension or a dry powder. Any systemdeveloped for the delivery of solutions, suspensions or dry powders viaoral or nasal inhalation or insufflation are suitable for theadministration of the present compounds.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

The present compounds are orally active compounds, and are preferablyorally administered.

The exact dosage, the therapeutically effective amount and frequency ofadministration depends on the particular compound of formula (I) or (I′)used, the particular condition being treated, the severity of thecondition being treated, the age, weight, sex, extent of disorder andgeneral physical condition of the particular patient as well as othermedication the individual may be taking, as is well known to thoseskilled in the art.

Furthermore, it is evident that said effective daily amount may belowered or increased depending on the response of the treated subjectand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention.

When used as a medicament to prevent or treat Alzheimer's disease, thecompounds of formula (I) or (I′) may be used in combination with otherconventional drugs used to combat Alzheimer's disease, such asgalantamine, donepezil, rivastigmine or tacrine. Thus, the presentinvention also relates to the combination of a compound of formula (I)or (I′) and another agent capable of preventing or treating Alzheimer'sdisease. Said combination may be used as a medicine. The presentinvention also relates to a product containing (a) a compound of formula(I) or (I′), and (b) another agent capable of preventing or treatingAlzheimer's disease, as a combined preparation for simultaneous,separate or sequential use in the prevention or treatment of Alzheimer'sdisease. The different drugs may be combined in a single preparationtogether with pharmaceutically acceptable carriers.

When used as a medicament to prevent or treat type 2 diabetes, thecompounds of formula (I) or (I′) may be used in combination with otherconventional drugs used to combat type 2 diabetes, such asglibenclamide, chlorpropamide, gliclazide, glipizide, gliquidon,tolbutamide, metformin, acarbose, miglitol, nateglinide, repaglinide,acetohexamide, glimepiride, glyburide, tolazamide, troglitazone,rosiglitazone, pioglitazone, isaglitazone.

Thus, the present invention also relates to the combination of acompound of formula (I) or (I′) and another agent capable of preventingor treating type 2 diabetes. Said combination may be used as a medicine.The present invention also relates to a product containing (a) acompound of formula (I) or (I′), and (b) another agent capable ofpreventing or treating type 2 diabetes, as a combined preparation forsimultaneous, separate or sequential use in the prevention or treatmentof type 2 diabetes. The different drugs may be combined in a singlepreparation together with pharmaceutically acceptable carriers.

When used as a medicament to prevent or treat cancer, the compounds offormula (I) or (I′) may be used in combination with other conventionaldrugs used to combat cancer such as platinum coordination compounds forexample cisplatin or carboplatin; taxane compounds for examplepaclitaxel or docetaxel; camptothecin compounds for example irinotecanor topotecan; anti-tumour vinca alkaloids for example vinblastine,vincristine or vinorelbine; anti-tumour nucleoside derivatives forexample 5-fluorouracil, gemcitabine or capecitabine; nitrogen mustard ornitrosourea alkylating agents for example cyclophosphamide,chlorambucil, carmustine or lomustine; anti-tumour anthracyclinederivatives for example daunorubicin, doxorubicin or idarubicin; HER2antibodies for example trastzumab; and anti-tumour podophyllotoxinderivatives for example etoposide or teniposide; and antiestrogen agentsincluding estrogen receptor antagonists or selective estrogen receptormodulators preferably tamoxifen, or alternatively toremifene,droloxifene, faslodex and raloxifene; aromatase inhibitors such asexemestane, anastrozole, letrazole and vorozole; differentiating agentsfor example retinoids, vitamin D and DNA methyl transferase inhibitorsfor example azacytidine; kinase inhibitors for example flavoperidol andimatinib mesylate or farnesyltransferase inhibitors for example R115777.

Thus, the present invention also relates to the combination of acompound of formula (I) or (I′) and another agent capable of preventingor treating cancer. Said combination may be used as a medicine. Thepresent invention also relates to a product containing (a) a compound offormula (I) or (I′), and (b) another agent capable of preventing ortreating cancer, as a combined preparation for simultaneous, separate orsequential use in the prevention or treatment of cancer. The differentdrugs may be combined in a single preparation together withpharmaceutically acceptable carriers.

When used as a medicament to prevent or treat bipolar disorder, thecompounds of formula (I) or (I′) may be used in combination with otherconventional drugs used to combat bipolar disorder such as atypicalantipsychotics, anti-epileptica, benzodiazepines, lithium salts, forexample olanzapine, risperidone, carbamazepine, valproate, topiramate.

Thus, the present invention also relates to the combination of acompound of formula (I) or (I′) and another agent capable of preventingor treating bipolar disorder. Said combination may be used as amedicine. The present invention also relates to a product containing (a)a compound of formula (I) or (I′), and (b) another agent capable ofpreventing or treating bipolar disorder, as a combined preparation forsimultaneous, separate or sequential use in the prevention or treatmentof bipolar disorder. The different drugs may be combined in a singlepreparation together with pharmaceutically acceptable carriers.

When used as a medicament to prevent or treat inflammatory diseases, thecompounds of formula (I) or (I′) may be used in combination with otherconventional drugs used to combat inflammatory diseases such assteroids, cyclooxygenase-2 inhibitors, non-steroidal-anti-inflammatorydrugs, TNF-α antibodies, such as for example acetyl salicylic acid,bufexamac, diclofenac potassium, sulindac, diclofenac sodium, ketorolactrometamol, tolmetine, ibuprofen, naproxen, naproxen sodium, tiaprofenacid, flurbiprofen, mefenamic acid, nifluminic acid, meclofenamate,indomethacin, proglumetacine, ketoprofen, nabumetone, paracetamol,piroxicam, tenoxicam, nimesulide, fenylbutazon, tramadol, beclomethasonedipropionate, betamethasone, beclamethasone, budesonide, fluticasone,mometasone, dexamethasone, hydrocortisone, methylprednisolone,prednisolone, prednisone, triamcinolone, celecoxib, rofecoxib,infliximab, leflunomide, etanercept, CPH 82, methotrexate,sulfasalazine.

Thus, the present invention also relates to the combination of acompound of formula (I) or (I′) and another agent capable of preventingor treating inflammatory diseases. Said combination may be used as amedicine. The present invention also relates to a product containing (a)a compound of formula (I) or (I′), and (b) another agent capable ofpreventing or treating inflammatory diseases, as a combined preparationfor simultaneous, separate or sequential use in the prevention ortreatment of inflammatory disorders. The different drugs may be combinedin a single preparation together with pharmaceutically acceptablecarriers.

Experimental Part

Hereinafter, “DIPE” is defined as diisopropyl ether, “DMA” is defined asN,N-dimethylacetamide.

A. Preparation of the Intermediate Compounds

EXAMPLE A1

The Preparation of Intermediate 1

1,1,-Diethoxy-N,N-dimethylmethanamine (0.153 mol) was added over 15minutes to ethyl 2-oxopropanoate (0.153 mol) at room temperature whilevigorously stirring. The temperature was kept below 30° C. The reactionmixture was heated to 80° C. for 24 hours. The residue was purified bydistillation, yielding 9.8 g (37.4%) of intermediate 1.

EXAMPLE A2

The Preparation of Intermediate 2

A mixture of 4-amino-2-(2-phenylethoxy)benzonitrile (0.012 mol) in1,1′-oxybis[2-methoxyethane] (50 ml) was stirred at 100° C., cyanamide(1 ml) was added dropwise. The reaction mixture was stirred at 100° C.for 30 minutes and at room temperature overnight. Extra cyanamide (1 ml)was added and the reaction mixture was stirred at 100° C. for 24 hours.Extra cyanamide (1 ml) was added and the reaction mixture was stirredfurther at 100° C. for 24 hours. The solvent was evaporated. The residue(6.3 g) was purified by high-performance liquid chromatography overHyperprep C18 HS BDS (eluent: (0.5% NH₄Ac in H₂O/CH₃CN 90/10)/MeOH/CH₃CN75/25/0; 0/50/50; 0/0/100). The first fraction was collected and thesolvent was evaporated, yielding 1.36 g (42.6%) of intermediate 2.

EXAMPLE A3

The Preparation of Intermediate 3

To a solution of intermediate 2 (0.00477 mol) in DMA (30 ml),intermediate 1 (0.0057 mol) was added. The reaction mixture was stirredfor 1 hour at room temperature and overnight at 100° C. This mixture wasagain stirred at 100° C. for 24 hours and then cooled to roomtemperature. The residue was poured out in a saturated NaCl-solution(300 ml), filtered and washed with H₂O. The precipitate was dissolved in2-propanone and this solution was concentrated in vacuum. The obtainedsolid was crystallized from EtOH, filtered and dried at 40° C. undervacuum, yielding 0.64 g (35.8%) of intermediate 3.

B. Preparation of the Final Compounds

EXAMPLE B1

Preparation of Compound 1

A mixture of 4-amino-2-(phenylmethoxy)-benzonitrile (0.0026 mol) and2-chloro-3-pyridinecarboxamide (0.0026 mol) was stirred at 150° C. for10 minutes, taken up in CH₂Cl₂/CH₃OH and washed with H₂O. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (1.2 g) was purified by column chromatographyover silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.1; 15–351 μm). Thepure fractions were collected and the solvent was evaporated. Theresidue (0.21 g) was crystallized from CH₃OH/diethyl ether. Theprecipitate was filtered off and dried, yielding 0.2 g of compound 1(22%) (mp.: 232° C.).

EXAMPLE B2

a) Preparation of Compound 2

A mixture of intermediate 3 (0.0027 mol) in NH₃/CH₃OH (30 ml) wasstirred for 1 day at room temperature. The resulting precipitate wasfiltered off, washed with methanol and DIPE, then dried (vacuum, 50°C.), yielding 0.600 g of compound 2 (65%).

b) Preparation of Compound 3

Intermediate 3 (0.0027 mol) in CH₃NH₂ in EtOH (15 ml) was stirred atroom temperature for 1 day. The precipitate was filtered off, washedwith MeOH and DIPE and dried (50° C., vacuum), yielding 0.7 g ofcompound 3.

c) Preparation of Compound 4

A mixture of intermediate 3 (0.0027 mol) and (CH₃)₂NH (1.2 g) in EtOH(40 ml) was stirred at room temperature for 3 days. The solvent wasevaporated and the residue was purified by flash column chromatographyover silica gel (eluent:CH₂Cl₂/MeOH 99.5/0.5; 99/1). The productfractions were collected and the solvent was evaporated. The residue wasstirred in DIPE and the formed precipitate was filtered off, washed anddried (50° C., vacuum), yielding 0.21 g of compound 4.

EXAMPLE B3

a) Preparation of Compound 5

A mixture of

(compound 6; prepared according to Example B2a)) (0.016 mol),1-(chloromethyl)-3-nitro-benzene (0.016 mol), K₂CO₃ (0.016 mol) and KI(catalytic quantity) in DMA (70 ml) was stirred at 60° C. for 1 day.

The reaction mixuture was concentrated under reduced pressure. Theresidue was stirred in H₂O. The precipitate was filtered off, washed anddried (vacuum; 60° C.), yielding 5.7 g of compound 5.

b) Preparation of Compound 7

Compound 5 (0.009 mol) in DMA (250 ml) was hydrogenated at roomtemperature with Pd/C 5% (1 g) as a catalyst in the presence ofthiophene solution (1 ml). After uptake of H₂ (3 equiv), the catalystwas filtered off and the solvent was evaporated, yielding 2.9 g ofcompound 7.

c) Preparation of Compound 8

A mixture of compound 7 (0.0028 mol) and Et₃N (0.0031 mol) in DMA (25ml) was stirred at room temperature. N,N-dimethylsulfamoyl chloride(0.0031 mol) was added dropwise at room temperature and the mixture wasstirred for 1 day. More Et₃N (0.0031 mol) and N,N-dimethylsulfamoylchloride (0.0031 mol) were added and the mixture was stirred for anotherday at room temperature. The solvent was evaporated. The residue waspurified by high performance liquid chromatography over hyperprep C18BDS (eluent: (0.5% NH₄OAc in H₂O/CH₃CN 90/10)/MeOH/CH₃CN 75/25/0;0/50/50; 0/0/100). The desired fractions were collected and the solventwas evaporated. The residue was stirred in DIPE. The precipitate wasfiltered off, washed and dried (vacuum; 50° C.), yielding 0.08 g ofcompound 8.

Tables 1 and 2 list the compounds of formula (I) which were preparedaccording to one of the above examples.

TABLE 1

Comp. Exp. no no. X—R² R³ R^(4a) R^(4b) 2 B2a —O—CH₂C₆H₅ —CN H H 3 B2b—O—CH₂C₆H₅ —CN CH₃ H 9 B3a

—CN H H 10 B3a

—CN H H 11 B3a

—CN H H 12 B3a —O—CH₂CH₂N(CH₃)₂ —CN H H 13 B3a

—CN H H 14 B3a

—CN H H 15 B3a

—CN H H 16 B3a

—CN H H 17 B3a

—CN H H 18 B3a

—CN H H 19 B3a

—CN H H 20 B3a

—CN H H 21 B3a

—CN H H 22 B3a

—CN H H 23 B3a

—CN H H 24 B3a

—CN H H 25 B2a

H H H 26 B3a

—CN H H 27 B3a

—CN H H 28 B3a —CN H H 29 B2a —H —CN H H 4 B2c

—CN CH₃ CH₃ 30 B3a

—CN H H 31 B3a

—CN H H 32 B3a

—CN H H 33 B3a

—CN H H 34 B3a

—CN H H 35 B3a

—CN H H 36 B3a

—CN H H 37 B3a

—CN H H 38 B3a

—CN H H 6 B2a —OH —CN H H 5 B3a

—CN H H 7 B3b

—CN H H 8 B3c

—CN H H

TABLE 2

Comp.no Exp.no.

R³ Physicaldata 1 B1

—CN 39 B2a

—CN 40 B1

—CN 41 B2a

—CN mp.: 217° C.C. Pharmacological Example

The pharmacological activity of the present compounds was examined usingthe following test.

GSK3beta assays were performed at 25° C. in a 100 μl reaction volume of25 mM Tris (pH 7.4) containing 10 mM MgCl₂, 1 mM DTT, 0.1 mg/ml BSA, 5%glycerol and containing 19 nM GSK3β, 5 μM biotinylated phosphorylatedCREB peptide, 1 μM ATP, 2 nM ATP-P³³ and a suitable amount of a testcompound of formula (I) or (I′). After one hour, the reaction wasterminated by adding 70 μl of Stop mix (1 mM ATP, 18 mg/ml streptavidincoated PVT SPA bead pH 11.0). The beads to which the phosphorylated CREBpeptide is attached were allowed to settle for 30 minutes and theradioactivity of the beads was counted in a microtiterplatescintillation counter and compared with the results obtained in acontrol experiment (without the presence of a test compound) in order todetermine the percentage of GSK3β inhibition. The IC₅₀ value, i.e. theconcentration (M) of the test compound at which 50% of GSK3β isinhibited, was calculated from the dose response curve obtained byperforming the above-described GSK3β assay in the presence of differentamounts of the test compound.

Table 3 list pIC₅₀ values (-log IC₅₀ (M)) obtained in theabove-described test for the present compounds.

TABLE 3 Comp. No. pIC₅₀ 12 6.05 19 6.34 26 6.36 36 6.39 9 6.42 11 6.5817 6.61 22 6.63 34 6.75 28 6.79 35 6.81 29 6.83 14 6.86 15 6.88 10 6.9631 7.02 25 7.04 23 7.09 32 7.19 18 7.24 3 7.26 38 7.26 13 7.28 2 7.30 247.32 30 7.33 16 7.41 21 7.60 8 7.68

1. A compound of formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein R¹ ishydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;C₁₋₆alkyloxyC₁₋₆alkylcarbonyl optionally substituted withC₁₋₆alkyloxycarbonyl; X is —NR¹—; —NH—NH—; —N═N—; —O—; —C(═O)—; —C(═S)—;—O—C(═O)—; —C(═O)—O—; —O—C(═O)—C₁₋₆alkyl-; —C(═O)—O—C₁₋₆alkyl-;—O—C₁₋₆alkyl-C(═O)—; —C(═O)—C₁₋₆alkyl-O—; —O—C(═O)—NR¹—; —NR¹—C(═O)—O—;—O—C(═O)—C(═O)—; —C(═O)—NR¹—, —NR¹—C(═O)—; —C(═S)—NR¹—, —NR¹—C(═S)—;—NR¹—C(═O)—NR¹—; —NR¹—C(═S)—NR¹—; —NR¹—S(═O)—NR¹—; —NR¹—S(═O)₂—NR¹—;—C₁₋₆alkyl-C(═O)—NR¹—; —O—C₁₋₆alkyl-C(═O)—NR¹—; —C₁₋₆alkyl-O—C(═O)—NR¹—;—C₁₋₆alkyl-; —O—C₁₋₆alkyl-; —C₁₋₆alkyl-O—; —NR¹—C₁₋₆alkyl-;—C₁₋₆alkyl-NR¹—; —NR₁—C₁₋₆alkyl-NR¹—; —NR¹—C₁₋₆alkyl-C₃₋₇cycloalkyl-;—C₂₋₆alkenyl-; —C₂₋₆alkynyl-; —O—C₂₋₆alkenyl-; —C₂₋₆alkenyl-O—;—NR¹—C₂₋₆alkenyl-; —C₂₋₆alkenyl-NR¹—; —NR¹—C₂₋₆alkenyl-NR¹—;—NR¹—C₂₋₆alkenyl-C₃₋₇cycloalkyl-; —O—C₂₋₆alkynyl-; —C₂₋₆alkynyl-O—;—NR¹—C₂₋₆alkynyl-; —C₂₋₆alkynyl-NR¹—; —NR¹—C₂₋₆alkynyl-NR¹—;—NR¹—C₂₋₆alkynyl-C₃₋₇cycloalkyl-; —O—C₁₋₆alkyl-O—; —O—C₂₋₆alkenyl-O—;—O—C₂₋₆alkynyl-O—; —CHOH—; —S—; —S(═O)—; —S(═O)₂—; —S(═O)—NR¹—;—S(═O)₂—NR¹—; —NR¹—S(═O)—; —NR¹—S(═O)₂—; —S—C₁₋₆alkyl-; —C₁₋₆alkyl-S—;—S—C₂₋₆alkenyl-; —C₂₋₆alkenyl-S—; —S—C₂₋₆alkynyl-; —C₂₋₆alkynyl-S—;—O—C₁₋₆alkyl-S(═O)₂— or a direct bond; R² is hydrogen, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, R²⁰, each of said groups representing R² mayoptionally be substituted where possible with one or more substituentseach independently being selected from ═S; ═O; R¹⁵; hydroxy; halo;nitro; cyano; R¹⁵—O—; SH; R¹⁵—S—; formyl; carboxyl; R¹⁵—C(═O)—;R¹⁵—O—C(═O)—; R¹⁵—C(═O)—O—; R¹⁵—O—C(═O)—O—; —SO₃H; R¹⁵—S(═O)—;R¹⁵—S(═O)₂—; R⁵R⁶N; R⁵R⁶N—C₁₋₆alkyl; R⁵R⁶N—C₃₋₇cycloalkyl;R⁵R⁶N—C₁₋₆alkyloxy; R⁵R⁶N—C(═O)—; R⁵R⁶N—C(═S)—; R⁵R⁶N—C(═O)—NH—;R⁵R⁶N—C(═S)—NH—; R⁵R⁶N—S(═O)_(n)—; R⁵R⁶N—S(═O)_(n)—NH—; R¹⁵—C(═S)—;R¹⁵—C(═O)—NH—; R¹⁵—O—C(═O)—NH—; R¹⁵—S(═O)_(n)—NH—; R¹⁵—O—S(═O)_(n)—NH—;R¹⁵—C(═S)—NH—; R¹⁵—O—C(═S)—NH—; R¹⁷R¹⁸N—Y_(1a)—; R¹⁷R¹⁸N—Y₂—NR¹⁶—Y₁—;R¹⁵—Y₂—NR¹⁹—Y₁—; H—Y₂—NR¹⁹—Y₁—; R³ is hydrogen; hydroxy; halo;C₁₋₆alkyl; C₁₋₆alkyl substituted with cyano, hydroxy or —C(═O)R⁷;C₂₋₆alkenyl; C₂₋₆alkenyl substituted with one or more halogen atoms orcyano; C₂₋₆alkynyl; C₂₋₆alkynyl substituted with one or more halogenatoms or cyano; C₁₋₆alkyloxy; C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl;C₁₋₆alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- ordi(C₁₋₆alkyl)amino; polyhaloC₁₋₆alkyl; polyhaloC₁₋₆alkyloxy;polyhaloC₁₋₆alkylthio; R²¹; R²¹—C₁₋₆alkyl; R²¹—O—; R²¹—S—; R²¹—C(═O)—;R²¹—S(═O)_(p)—; R⁷—S(═O)_(p)—; R⁷—S(═O)_(p)—NH—; R²¹—S(═O)_(p)—NH—;R⁷—C(═O)—; —NHC(═O)H; —C(═O)NHNH₂; R⁷—C(═O)—NH—; R²¹—C(═O)—NH—;—C(═NH)R⁷; —C(═NH)R²¹; R^(4a) or R^(4b) each independently are hydrogen,R⁸, —Y₁—NR⁹—Y₂—NR¹⁰R¹¹, —Y₁—NR⁹—Y₁—R⁸, —Y₁—NR⁹R¹⁰; R⁵ and R⁶ eachindependently are hydrogen, R⁸, —Y₁—NR⁹—Y₂—NR¹⁰R¹¹, —Y₁—NR⁹—Y₁—R⁸,—Y₁—NR⁹R¹⁰, or R⁵ and R⁶ may together with the nitrogen to which theyare attached form a saturated or partially saturated monocyclic 3 to 8membered heterocycle or an aromatic 4 to 8 membered monocyclicheterocycle, each of said heterocycles may optionally be substitutedwith one or more substituents selected from R¹², R¹³ and R¹⁴, or each ofsaid heterocycles may optionally be fused with a benzene ring, saidbenzene ring being optionally substituted with one or more substituentsselected from R¹², R¹³ and R¹⁴; R⁷ is C₁₋₆alkyl, C₁₋₆alkyloxy, amino,mono- or di(C₁₋₆alkyl)amino or polyhaloC₁₋₆alkyl; R⁸ is C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆alkynyl; a monocyclic, bicyclic or tricyclic saturatedcarbocycle; a monocyclic, bicyclic or tricyclic partially saturatedcarbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; amonocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic,bicyclic or tricyclic partially saturated heterocycle; a monocyclic,bicyclic or tricyclic aromatic heterocycle; C₁₋₆alkyl substituted with amonocyclic, bicyclic or tricyclic saturated carbocycle or with amonocyclic, bicyclic or tricyclic partially saturated carbocycle or witha monocyclic, bicyclic or tricyclic aromatic carbocycle or with amonocyclic, bicyclic or tricyclic saturated heterocycle or with amonocyclic, bicyclic or tricyclic partially saturated heterocycle orwith a monocyclic, bicyclic or tricyclic aromatic heterocycle; each ofsaid groups representing R⁸ may optionally be substituted with one ormore substituents selected from R¹², R¹³ and R¹⁴; R⁹, R¹⁰ and R¹¹ eachindependently are hydrogen or R⁸, or any two of R⁹, R¹⁰ and R¹¹ maytogether be C₁₋₆alkanediyl or C₂₋₆alkenediyl thereby forming a saturatedor partially saturated monocyclic 3 to 8 membered heterocycle or anaromatic 4 to 8 membered monocyclic heterocycle together with thenitrogen atoms to which they are attached, each of said heterocycles mayoptionally be substituted with one or more substituents selected fromR¹², R¹³ and R¹⁴; R¹², R¹³ and R¹⁴ each independently are hydrogen; R¹⁵;hydroxy; halo; nitro; cyano; R¹⁵—O—; SH; R¹⁵—S—; formyl; carboxyl;R¹⁵—C(═O)—; R¹⁵—O—C(═O)—; R¹⁵—C(═O)—O—; R¹⁵—O—C(═O)—O—; —SO₃H;R¹⁵—S(═O)—; R¹⁵—S(═O)₂—; R¹⁵R¹⁶N—S(═O)—; R¹⁵R¹⁶N—S(═O)₂—; R¹⁷R¹⁸N—Y₁—;R¹⁷R¹⁸N—Y₂—NR¹⁶—Y₁—; R¹⁵—Y₂—NR¹⁹—Y₁—; H—Y₂—NR¹⁹—Y₁—; oxo, or any two ofR¹², R¹³ and R¹⁴ may together be C₁₋₆alkanediyl or C₂₋₆alkenediylthereby forming a saturated or partially saturated monocyclic 3 to 8membered carbo—or heterocycle or an aromatic 4 to 8 membered monocycliccarbo—or heterocycle together with the atoms to which they are attached,or any two of R¹², R¹³ and R¹⁴ may together be —O—(CH₂)_(r)—O— therebyforming a saturated, partially saturated or aromatic monocyclic 4 to 8membered carbo—or heterocycle together with the atoms to which they areattached; R¹⁵ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, a monocyclic,bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic ortricyclic partially saturated carbocycle; a monocyclic, bicyclic ortricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclicsaturated heterocycle; a monocyclic, bicyclic or tricyclic partiallysaturated heterocycle; a monocyclic, bicyclic or tricyclic aromaticheterocycle; C₁₋₆alkyl substituted with a monocyclic, bicyclic ortricyclic saturated carbocycle or with a monocyclic, bicyclic ortricyclic partially saturated carbocycle or with a monocyclic, bicyclicor tricyclic aromatic carbocycle or with a monocyclic, bicyclic ortricyclic saturated heterocycle or with a monocyclic, bicyclic ortricyclic partially saturated heterocycle or with a monocyclic, bicyclicor tricyclic aromatic heterocycle; each of said substituentsrepresenting R¹⁵ may optionally be substituted with one or moresubstituents selected from R¹², R¹³ and R¹⁴; or each of said carbocyclesor heterocycles may optionally be fused with a benzene ring, saidbenzene ring being optionally substituted with one or more substituentsselected from R¹², R¹³ and R¹⁴; R¹⁶, R¹⁷, R¹⁸ and R¹⁹ each independentlyare hydrogen or R¹⁵, or R¹⁷ and R¹⁸, or R¹⁵ and R¹⁹ may together beC₁₋₆alkanediyl or C₂₋₆alkenediyl thereby forming a saturated orpartially saturated monocyclic 3 to 8 membered heterocycle or anaromatic 4 to 8 membered monocyclic heterocycle, each of saidheterocycles may optionally be substituted with one or more substituentsselected from R¹², R¹³ and R¹⁴; or R¹⁷ and R¹⁸ together with R¹⁶ may beC₁₋₆alkanediyl or C₂₋₆alkenediyl thereby forming a saturated orpartially saturated monocyclic 3 to 8 membered heterocycle or anaromatic 4 to 8 membered monocyclic heterocycle together with thenitrogen atoms to which they are attached, each of said heterocycles mayoptionally be substituted with one or more substituents selected fromR¹², R¹³ and R¹⁴; R²⁰ is a monocyclic, bicyclic or tricyclic saturatedcarbocycle; a monocyclic, bicyclic or tricyclic partially saturatedcarbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; amonocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic,bicyclic or tricyclic partially saturated heterocycle; a monocyclic,bicyclic or tricyclic aromatic heterocycle; R²¹ is a monocyclic,bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic ortricyclic partially saturated carbocycle; a monocyclic, bicyclic ortricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclicsaturated heterocycle; a monocyclic, bicyclic or tricyclic partiallysaturated heterocycle; a monocyclic, bicyclic or tricyclic aromaticheterocycle, each of said carbocycles or heterocycles representing R²¹may optionally be substituted with one or more substituents selectedfrom R¹², R¹³ and R¹⁴; Y_(1a) is —Y₃—S(═O)—Y₄—; —Y₃—S(═O)₂—Y₄—,—Y₃—C(═O)—Y₄—, —Y₃—C(═S)—Y₄—, —Y₃—O—Y₄—, —Y₃—S—Y₄—, —Y₃—O—C(═O)—Y₄— or—Y₃—C(═O)—O—Y₄—; Y₁ or Y₂ each independently are a direct bond,—Y₃—S(═O)—Y₄—; —Y₃—S(═O)₂—Y₄—, —Y₃—C(═O)—Y₄—, —Y₃—C(═S)—Y₄—, —Y₃—O—Y₄—,—Y₃—S—Y₄—, —Y₃—O—C(═O)—Y₄— or —Y₃—C(═O)—O—Y₄—; Y₃ or Y₄ eachindependently are a direct bond, C₁₋₆alkanediyl, C₂₋₆alkenediyl orC₂₋₆alkynediyl; n is 1 or 2; m is 1 or 2; p is 1 or 2; r is 1 to 5; s is1 to 3; aryl is phenyl or phenyl substituted with one, two, three, fouror five substituents each independently selected from halo, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl andpolyhaloC₁₋₆alkyloxy; provided that —X—R² and/or R³ is other thanhydrogen; and provided that the following compoundN-phenyl-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinecarboxamide isnot included.
 2. A compound as claimed in claim 1 wherein R³ is otherthan C₁₋₆alkyloxy or polyhaloC₁₋₆alkyloxy.
 3. A compound as claimed inclaim 1 provided that —X— is other than a direct bond or —C₁₋₆alkyl-. 4.A compound as claimed in claim 1 wherein the compound has the followingformula


5. A compound as claimed in claim 1 wherein the compound has thefollowing formula


6. A compound as claimed in claim 1 wherein the compound is2-[[4-cyano-3-[[(dimethylamino)sulfonyl]amino]phenyl]methoxy]phenyl]amino]-4-pyrimidinecarboxamide;2-[[4-cyano-3-[(2-quinolinylmethoxy)phenyl]amino]-4-pyrimidinecarboxamide;2-[[4-cyano-3-[2-(4-fluorophenoxy)propoxy]phenyl]amino]-4-pyrimidinecarboxamide;2-[[4-cyano-3-[(2-methoxyphenyl)methoxy]phenyl]amino]-4-pyrimidinecarboxade;2-[[4-cyano-3-[(1-ethyl-1H-imidazol-2-yl)methoxy]phenyl]amino-4-pyrimidinecarboxamide;2-[[4-cyano-3-(phenylmethoxy)phenyl]amino]4-pyrimidinecarboxamide;2-[[4-cyano-3-[(4-methoxyphenyl)methoxy]phenyl]amino]-4-pyrimidinecarboxamide;2-[[4-cyano-3-(2-naphthalenylmethoxy)phenyl]amino]-4-pyrimidinecarboxamide;a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof.
 7. A compositioncomprising a pharmaceutically acceptable carrier and as activeingredient a therapeutically effective amount of a compound as claimedin claim
 1. 8. A process for preparing a compound as claimed in claim 1,wherein a) reacting an intermediate of formula (II) with an intermediateof formula (III) in the presence of a suitable solvent and optionally inthe presence of a suitable acid or a suitable base

 with W1 representing a suitable leaving group and with R1, R2, R3, R4a,R4b, X, Z, s and ring A as defined in claim 1; b) reacting anintermediate of formula (IV) with an intermediate of formula (V)optionally in the presence of a suitable solvent

 with W2 representing a suitable leaving group and with R1, R2, R3, R4a,R4b, X, Z, s and ring A as defined in claim 1; c) reacting anintermediate of formula (VI) with an intermediate of formula (VII) inthe presence of a suitable solvent

 with W3 representing a suitable leaving group and with R1, R2, R3, R4a,R4b, X, s and ring A as defined in claim 1; d) reacting an intermediateof formula (VIII) with a suitable oxidizing agent in the presence of asuitable solvent and optionally in the presence of a suitable base

 with R1, R2, R3, X, s and ring A as defined in claim
 1. 9. The processof claim 8 wherein the compound of formula (I) is converted into atherapeutically active non-toxic acid addition salt by treatment with anacid.
 10. The process of claim 8 wherein the compound of formula (I) isconverted into a therapeutically active non-toxic base addition salt bytreatment with a base.
 11. The process of claim 9 wherein thetherapeutically active acid addition salt of compound of formula (I) isconvened into a free base by treatment with an alkali.
 12. The processof claim 10 wherein the therapeutically active non-toxic base additionsalt of compound of formula (I) is converted into a free acid bytreatment with acid.
 13. The process of claim 8 wherein the compounds offormula (I) are prepared as stereochemically isomeric forms, N-oxides,salts, solvates or quaternary amines.